Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges

Wang, Man; Yu, Fei; Zhang, Yuan

doi:10.1186/s12943-024-02214-5

Review
Open access
Published: 18 January 2025

Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges

Man Wang¹,
Fei Yu¹ &
Yuan Zhang¹

Molecular Cancer volume 24, Article number: 26 (2025) Cite this article

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Abstract

Clinically, multimodal therapies are adopted worldwide for the management of cancer, which continues to be a leading cause of death. In recent years, immunotherapy has firmly established itself as a new paradigm in cancer care that activates the body’s immune defense to cope with cancer. Immunotherapy has resulted in significant breakthroughs in the treatment of stubborn tumors, dramatically improving the clinical outcome of cancer patients. Multiple forms of cancer immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapy and cancer vaccines, have become widely available. However, the effectiveness of these immunotherapies is not much satisfying. Many cancer patients do not respond to immunotherapy, and disease recurrence appears to be unavoidable because of the rapidly evolving resistance. Moreover, immunotherapies can give rise to severe off-target immune-related adverse events. Strategies to remove these hindrances mainly focus on the development of combinatorial therapies or the exploitation of novel immunotherapeutic mediations. Nanomaterials carrying anticancer agents to the target site are considered as practical approaches for cancer treatment. Nanomedicine combined with immunotherapies offers the possibility to potentiate systemic antitumor immunity and to facilitate selective cytotoxicity against cancer cells in an effective and safe manner. A myriad of nano-enabled cancer immunotherapies are currently under clinical investigation. Owing to gaps between preclinical and clinical studies, nano-immunotherapy faces multiple challenges, including the biosafety of nanomaterials and clinical trial design. In this review, we provide an overview of cancer immunotherapy and summarize the evidence indicating how nanomedicine-based approaches increase the efficacy of immunotherapies. We also discuss the key challenges that have emerged in the era of nanotechnology-based cancer immunotherapy. Taken together, combination nano-immunotherapy is drawing increasing attention, and it is anticipated that the combined treatment will achieve the desired success in clinical cancer therapy.

Introduction

Cancer remains a major public health challenge globally, and the future burden of cancer is expected to increase because of population growth and lifestyle changes [1]. According to the global cancer observatory data (GLOBOCAN), over 19.3 million new cancer cases were reported, resulting in approximately 10 million deaths in 2020 [2]. Conventional cancer therapies, such as chemotherapy and radiotherapy, show limited efficacy and applicability, hence highlighting the urgency for seeking more effective therapeutic measures [3]. The body immune defense system is the most powerful weapon against cancer [4]. Over the past decades, cancer immunotherapy has emerged as a beneficial treatment strategy for cancer and rejuvenated the field of cancer immunology [5]. Several immunotherapeutic methodologies, including cancer peptide vaccines, monoclonal antibodies and immune checkpoint inhibitors (ICIs), have changed the classic cancer care landscape [6,7,8,9]. These immunotherapies have achieved remarkable clinical responses. Nevertheless, their efficacies vary, and only a small proportion of cancer patients can benefit from these immunotherapies. There are many reasons for the limited efficacy of immunotherapy in the clinical setting. First of all, immunotherapeutic approaches have some kinds of disadvantages including low targeting ability and unwanted adverse effects that hinder their clinical application [10, 11]. Secondly, immunotherapies work by releasing the brakes on the host immune system, allowing it to destroy cancer cells [12]. However, this can also cause the immune system to mistakenly attack normal cells and tissues, resulting in severe or even fatal immune-related adverse events [13]. Thirdly, cancer immune escape and resistant mechanisms may overpower immunotherapeutic modalities under certain conditions and contribute to unsatisfactory outcomes of cancer immunotherapy [14]. In addition, it is challenging to deliver therapeutic agents or immune cells into tumor sites through an immunosuppressive tumor microenvironment (TME) [15, 16]. Particularly, application of immune cell therapy to solid tumors has proven far more arduous, as solid tumors usually exclude immune cells [17]. Thus, the rational design and development of advanced cancer immunotherapies remain a huge challenge.

At present, the medical and research communities have attempted alternative strategies to address the aforementioned limitations. One of the emerging area in this field is nano-immunotherapy, which potentiates anticancer immune responses and sensitizes tumors to immunotherapy [18]. Specifically, targeted or stimuli-responsive nanocarriers are generated to transport bioactive agents in their native conformations to the target site, which amplify their anticancer efficacy and extend the survival of cancer patients [19]. Nanodrug delivery platforms offer numerous advantages in cancer treatment, including high stability and biocompatibility, enhanced permeability and retention (EPR) effect, reduced adverse effects, and precise targeting of cancer cells [20,21,22]. With the deepening and expansion of research, nano-immunotherapy has become a new hotspot and trend in recent years. In this review, we summarize recent research advances in nano-immunotherapy and focus on the mechanisms by which nanodrug delivery systems enhance the anticancer effects of conventional immunotherapies. We also discuss the challenges of nano-immunotherapy and critically analyze the outlook for this emerging field. Gaining insights into the roles of nanotechnology in increasing the efficacy of immunotherapies will provide valuable insights for the development of nanomedicine-based therapies aimed at improving patient outcomes.

Types of cancer immunotherapy

The cancer-immunity cycle is composed of a series of functional stepwise events that are required for immune-mediated control of cancer growth (Fig. 1) [23]. The cancer-immunity cycle is initiated by the liberation of antigens from dead cancer cells [24]. Cancer-derived antigens are taken up by antigen-presenting cells (APCs), such as dendritic cells (DCs) [25]. APCs process cancer-associated antigens into smaller peptides [26]. These peptides are exhibited on the surface of APCs, along with major histocompatibility complex (MHC) molecules [27]. Afterwards, these APCs migrate to the nearest draining lymph node (DLN), where they present cancer-specific antigens to T cells [28]. Effector T cells are primed and activated after recognition of peptide/MHC complexes by T cell receptors (TCRs) [29]. Activated T cells then move to the tumor through the circulation, infiltrate into the tumor and eliminate cancer cells [24]. Effector T cells can directly kill cancer cells through the perforin/granzyme-dependent granule exocytosis mechanism or the extrinsic death receptor pathway [30]. Once cancer cells die, additional neoantigens are released to actuate a new round of the cancer-immunity cycle [31]. The cancer-immunity cycle highlights the tremendous potential of immunotherapy in cancer treatment. Immunotherapy has recently gained considerable attention due to its high efficacy and low toxicity. Based on the critical mechanisms of the cancer immune cycle, current cancer immunotherapies mainly include ICIs, adoptive cell therapy, antibody-based targeted therapy, cancer vaccines, oncolytic viruses and cytokine therapy (Fig. 2) [32].

Immune checkpoint inhibitors

Immune checkpoint molecules are a series of inhibitory and stimulatory molecules expressed on cancer cells and immune cells [33]. They act as physiological brakes of the immune system, which are required to maintain immune homeostasis and prevent autoimmunity. Cancer cells have evolved to utilize immune checkpoints to evade immune surveillance [34, 35]. Therefore, checkpoint molecules represent prospective therapeutic targets for cancer management. ICIs can enhance antitumor immune responses by suppressing negative modulators of the immune response. Programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are the most well studied among immune checkpoint molecules, and their inhibitors have been used as a therapeutic regimen in the clinical intervention of several cancers [36]. Other potential molecules and their ligands, including B and T lymphocyte attenuator (BTLA), lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3), are also considered as prospective targets for immune checkpoint blockade therapy [37]. Despite the fact that ICI treatments exhibit durable clinical efficacy against a wide range of cancers, checkpoint inhibition has not fulfilled its early promise. This is due to the common occurrence of severe adverse events in various organs and low efficiency associated with ICIs [38, 39]. Low counts of tumor-infiltrating T cells, aberrant regulation of immune checkpoints in both cancer cells and T cells, and acquired resistance to checkpoint blockade may contribute to limited responsiveness to ICIs.

Adoptive cell therapy

Adoptive cell therapy has emerged as one of the most promising cellular immunotherapies, which involves the intravenous adoptive transfer of autologous or allogeneic tumor-infiltrating lymphocytes (TILs), TCR-modified T cells, or chimeric antigen receptors (CARs) into patients [40]. Early studies exploring the application of adoptive cell therapy for cancer treatment primarily concentrated on TILs. TILs are able to recognize antigens on the surface of cancer cells. In TIL therapy, naturally occurring TILs are collected, genetically activated, and undergo ex vivo expansion. Subsequently, the TILs are transplanted back into the TME of cancer patients, where they elicit robust antitumor responses, contributing to cancer regression [41]. Although TIL therapy holds great promise for cancer treatment, it still faces many challenges [42]. The frequencies of TILs are very low in cancers, and thus they require extensive ex vivo expansion [43]. The success rates of ex vivo TIL expansion vary among cancer patients [44]. In some patients, TILs cannot reach the necessary quantities for therapeutic use [45]. To surmount these constraints and harness the full potential of adoptive cell therapy, innovative strategies utilizing peripheral lymphocytes have emerged. The instinctive anticancer potential of these cells may be further enhanced through genetic engineering. In most clinical studies, peripheral blood T cells are genetically modified to express a specific TCR or a synthetic CAR [46]. TCR-modified T cells can specifically recognize cancer antigens in a MHC-dependent manner [47, 48]. TCR gene therapy specifically targeted various cancer antigens, such as melanoma differentiation antigens, C/T antigens, and carcinoembryonic antigen (CEA) [49,50,51]. It demonstrated clinical efficacy in patients with melanoma, synovial sarcoma, or colorectal adenocarcinoma. Nevertheless, engineered TCR-T cells cannot differentiate between cancer cells and normal cells expressing target antigens/epitopes, thus TCR gene therapy may damage the corresponding normal tissues. For instance, patients with metastatic colorectal cancer (CRC) that received CEA reactive TCR-T cells were reported to develop inflammatory colitis, which was induced by T cell recognition of CEA in colonic mucosa [51]. TCR-T cells targeting MART-1 and MAGE-A3 caused fatal cardiotoxicity in patients with metastatic melanoma, owing to the high abundance of these two antigens in heart tissue [52, 53]. Anti-MAGE-A3 TCR gene therapy resulted in severe mental disorders in patients with metastatic melanoma due to the cross reaction of TCR-T cell with MAGE-A12 in normal brain tissue [50]. Identifying antigens restricted to tumors can help improve the efficacy and safety of TCR gene therapy [54]. The emergence of CAR-T treatment has revolutionized the field of cellular immunotherapy. CARs are synthetic membrane immune receptors that harbor an antigen recognition domain and an intracellular signaling domain [55]. CARs are capable of inducing lymphocyte activation and costimulation [56]. CAR-based immunotherapy has the potential for broad therapeutic applications in cancer treatment, as CARs interact with surface antigens on target cells in a manner similar to antibodies [57]. Moreover, CARs not only target proteins but also recognize lipids and carbohydrates, making them an ideal tool for adoptive cell therapy [57]. Reportedly, CAR-T therapy contributes to durable tumor growth control in patients with relapsed and refractory hematologic malignancies [56]. The undeniable toxicity and high costs associated with personalized T cell formation are likely to limit the widespread feasibility of CAR-T therapy. Additionally, antigen escape and early exhaustion of the CAR-T cell population are significant obstacles to the effectiveness of CAR-T-based immunotherapy [58].

As stated above, adoptive cell immunotherapy has shown clinical activity in several tumor types. However, the clinical benefits of this treatment modality in solid tumors appear to be limited. Some factors contribute to the suboptimal performance of T cell immunotherapy, including low efficiency of T cell transfer, limited activation and short persistence of infused T cells, and challenges in overcoming the hostile TME. Attempts to tackle these barriers have led to new approaches involving the blockade of inhibitory signals, optimization of cell culture, supplementation of cytokine costimulation, regulation of T cell metabolism, and integration of new genome-engineering technologies into cellular immunotherapies [59]. Ongoing research efforts will hopefully broaden the clinical application of adoptive cell therapy to various cancers.

Antibody-based targeted therapy

In recent years, monoclonal antibody-based immunotherapy has emerged as a potent clinical tool for the treatment of numerous cancers (Fig. 2), complementing chemotherapy, radiotherapy and surgery [60]. Three classes of monoclonal antibodies are used to enhance the immune system of cancer patients, including naked monoclonal antibodies, conjugated monoclonal antibodies, and bispecific monoclonal antibodies [61]. On the one hand, most naked monoclonal antibodies directly recognize antigens on cancer cells to activate antitumor immune reactions [62]. For instance, Alemtuzumab is a humanized monoclonal antibody that specifically targets the lymphocyte-specific surface marker CD52 and has been used in the treatment of chronic lymphocytic leukemia (CLL) [63]. On the other hand, naked monoclonal antibodies (e.g., cemiplimab, nivolumab, atezolizumab and avelumab) interact with immune checkpoint molecules (PD-1 and PD-L1) to suppress cancer immune evasion [64].

Conjugated monoclonal antibodies are paired with chemotherapy or a radioactive agent [65]. Monoclonal antibodies that are linked to chemotherapy are known as antibody–drug conjugates (ADCs) [66]. ADCs bind to specific antigens on cancer cell surface after they reach target cells. The ADC-antigen complex is subsequently taken up by cancer cells to form an early endosome through endocytosis [67]. The early endosome matures into a late endosome that eventually fuses with the lysosome. The chemotherapeutic drug is discharged from ADCs via either a chemical reaction or proteolytic enzyme-mediated degradation in the lysosome [68]. The released cytotoxic agent acts to induce apoptosis or cell death in cancer cells [69]. Monoclonal antibodies in ADCs exert immune-related cytotoxic effects, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [70]. Radiolabeled antibodies (radioimmunoconjugates) consist of a monoclonal antibody attached to a radionuclide [71]. In contrast to ADCs, radiolabeled antibodies may not require internalization. Once radiolabeled monoclonal antibodies recognize and bind to specific surface antigens on cancer cells, the emitted radionuclide leads to DNA strand breaks through the synthesis of free radicals, contributing to apoptosis and programmed necrosis in cancer cells [71]. Radiolabeled antibodies can achieve high response rates with low toxicity compared to other cancer therapies [72].

Bispecific monoclonal antibodies are engineered artificial antibodies with two binding sites directed at two distinct epitopes of one antigen simultaneously or two distinct antigens [73]. Bispecific monoclonal antibodies can target both cancer cells and immune cells [74]. They act directly on cancer cells to induce apoptosis and enhance the anticancer activity of immune cells, such as tumor-infiltrating T cells [75]. Bispecific monoclonal antibodies offer several advantages, including high specificity, low toxicity, and improved efficacy [74]. To date, several bispecific monoclonal antibodies, such as Amivantamab, Blinatumomab, and Candonilimab, have been approved for the treatment of cancer patients [76]. However, monoclonal antibody-based therapies have several limitations, including poor pharmacokinetics, inadequate target accessibility, high production cost, potential resistance and mutation, and the risk of side effects (e.g., cardiac toxicity, hypertension and thrombosis) [77,78,79,80]. These challenges faced by monoclonal antibodies restrict their use in clinical cancer care.

Cancer vaccines

The TME in different cancer patients is unique, and cancer cells express their own antigens to help differentiate themselves from noncancerous cells [81]. Some cancer antigens are ordinary proteins synthesized in large numbers [61]. Cancer antigens can also be novel ones due to gene mutations and solely expressed by cancer cells, which would be the target for directed vaccine responses [82]. Therapeutic cancer vaccines are capable of eliciting long-lasting antitumor immune responses by immunizing cancer patients against cancer-specific antigens [83]. Cancer vaccines enable the body’s immune system to recognize cancer-derive signals, thereby amplifying and diversifying the repertoire of tumor-specific T cells [84]. The most commonly used vaccines are peptide-based, consisting of immunogenic epitopes derived from tumor-associated or -specific antigens [85]. Synthetic long peptide (SLP) vaccines consist of 25–35 amino acids, encompassing various epitopes or a large fraction of the target protein [86]. Thus, SLP vaccines are expected to induce stronger immune responses compared to vaccines consisting of 8–12 amino acids derived from cancer antigens. The inclusion of cytokine adjuvants can further enhance the immune-activating effect of SLP vaccines. For instance, in a phase 1/2 trial involving 11 CRC patients, the addition of interferon-α (IFN-α) to a p53-SLP vaccine was well tolerated and induced stronger p53-specific T cell responses compared to p53-SLP alone [87]. The cell-based cancer vaccine is a type of cancer vaccine that utilizes the patient’s own immune cells. DCs, known as the most effective APCs, are considered an ideal carrier for cancer vaccines. DC vaccination can work by either directly targeting antigens to DC receptors or by generating antigen-loaded DCs ex vivo. Monocyte-derived DCs loaded with cancer cell lysates exhibited good tolerance and efficacy in patients with metastatic renal cell carcinoma (RCC) [88]. Although studies on cancer vaccines are ongoing, their practical applications are still limited due to various challenges, including identification of optimal candidates, development of antigen delivery platforms, assessment of immune responses, and the large-scale manufacturing of vaccines. So far, only one therapeutic DC-based cancer vaccine Provenge™, an autologous peripheral blood mononuclear cell (PBMC) product, has been approved for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) [89]. New attempts combining DC-based cancer vaccines with conventional cancer therapies are underway and early evidence appears promising [90]. Concerted efforts are being devoted to improving their anticancer benefits.

In the case of DNA vaccines, plasmids harboring cDNAs encoding cancer antigens are administered to cancer patients [91]. These antigens are expressed in cancer patients and induce T cell-mediated immune responses against them [92]. DNA vaccines demonstrate significant therapeutic efficacy in clinical trials. For instance, the DNA vaccine GX-188E was administered to patients with human papillomavirus (HPV)-positive advanced cervical cancer, and it exhibited a favorable safety profile [93]. Among the treated 26 patients, 11 patients achieved an overall response, with four experiencing complete remission and seven experiencing partial remission. In a phase 1 non-randomized clinical trial, the DNA vaccine encoding the intracellular domain of human epidermal growth factor receptor 2/neu (HER2/neu) induced long-lasting antigen-specific T cell responses in patients with advanced HER2/neu-positive breast cancer [94]. DNA vaccines must overcome multiple barriers to reach the cell nucleus, which poses a challenge for DNA-based antigen delivery vehicles. Moreover, DNA vaccines have shown limited immunogenicity in cancer patients [95]. DNA may be integrated into the host genome. mRNA vaccines demonstrate superiority over DNA vaccines in terms of a low risk of genome integration [96]. The personalized mRNA vaccine BNT122 triggered neoantigen-specific T cell responses and extended recurrence-free survival (RFS) in patients with pancreatic ductal adenocarcinoma (PDAC) [97]. Technical barriers to mRNA vaccines focus on their sequence design, in vivo stability and delivery approaches, as well as translation efficiency [98].

Oncolytic viruses

Oncolytic viruses are viruses that selectively replicate in and kill cancer cells while causing no damage to their normal cellular counterparts [99]. The anticancer effect of oncolytic viruses is mainly achieved in two ways: direct oncolysis and induction of antitumor immune responses [100]. Oncolytic viruses can be divided into naturally attenuated viral strains and genetically engineered viral vectors [101]. Modulating the viral vector or genome can potentially enhance the clinical efficacy of oncolytic viruses. In particular, oncolytic viruses armed with exogenous immune-stimulating molecules have shown significant tumor-antagonizing effects by synergistically activating antitumor immunity. Several oncolytic virus products have been developed for the clinical treatment of cancers. Rigvir, an unmodified enteric cytopathic human orphan virus type 7 (ECHO-7), was the first approved oncolytic agent for the treatment of melanoma [102]. In 2005, the China Food and Drug Administration (CFDA) approved Oncorine (H101), an engineered human adenovirus, for the treatment of advanced head and neck cancer [103]. However, the therapeutic efficacy of these two oncolytic drugs mainly depends on their oncolytic actions rather than immune-stimulating effects. Talimogene laherparepvec (T-VEC) is an attenuated herpes simplex virus-1 (HSV-1) encoding granulocyte–macrophage colony-stimulating factor (GM-CSF) and was approved for the treatment of melanoma in 2015 [104]. Delytact (G47∆), a triple-mutated oncolytic HSV-1, is used for the treatment of residual or recurrent glioblastoma [105]. Oncolytic viruses are an emerging class of immunotherapy in cancer. The overall performance of genetically modified oncolytic viruses is not as good as expected. Intratumoral injection, the common delivery approach for oncolytic viruses, may pose a risk of bleeding and unwanted metastasis at the lesion site [106]. Moreover, delivering therapeutic viruses into deep tumor tissues through intratumoral inoculation is arduous. Intravenous injection can be a feasible choice. Viruses administered intravenously may be exterminated by neutralizing antibodies in the circulation. In this case, incorporating or loading oncolytic viruses into special biomaterials is an effective solution. Normal human cells (e.g., mesenchymal stem cells (MSCs)) are potential carriers for oncolytic virus transportation [107].

Cytokine therapy

Cytokines are capable of regulating the immune system that mediate communication between immune cells. Three primary types of cytokines (IFNs, interleukins (ILs) and GM-CSFs) have been extensively investigated in clinical settings [108]. IFN-γ exerts an inhibitory effect on cancer cell proliferation and enhances antitumor immunity by promoting antigen presentation and strengthening the function of cytotoxic T lymphocytes (CTLs), macrophages and T helper 1 (Th1) cells [109]. ILs induce T cell growth to enhance antitumor immune responses [110,111,112]. GM-CSFs trigger adaptive immune responses by supporting T cell homeostasis and facilitating DC differentiation [113]. GM-CSFs have been used as medication to promote granulocyte recovery following chemotherapy [114]. These cytokine-based therapies induced the expansion and functionality of immune cells, thereby leading to good clinical outcomes in patients with melanoma and hematological malignancies [115, 116]. Additionally, immunotherapeutic strategies targeting cytokine signaling have been developed. Inhibitors of the transforming growth factor-β type I receptor (TGFβR1), such as SD-208, functioned to reinvigorate T cell function [117]. Stimulator of interferon genes (STING) agonists effectively triggered the production of proinflammatory cytokines and elicited type I IFN (IFN-I) responses [118].

Notably, due to the short half-life of cytokines, effective cytokine-based therapies generally require high-dose infusions, which can lead to vascular leakage and cytokine release syndrome [119]. This further restricts the long-term benefits of cytokine treatments. Moreover, cytokine-based therapeutics may result in autoimmune attacks against the body’s own tissues by supporting the survival of regulatory T (Treg) cells and inducing the death of activated T cells [120]. Therefore, current research is investigating combination treatment strategies, including the combination of two or more cytokines (e.g., IFNs coupled with ILs), and the combination of cytokines with other immunotherapies or chemotherapies, aiming to attenuate the side effects of high treatments dosages required for cytokine-directed monotherapy [121].

Clinically approved nano-based therapeutics for cancer therapy

Nanoparticles, which are defined as particles with diameters in the size range of 1–100 nanometers (nm), are composed of various biodegradable materials, such as lipids, metals, or polymers [122, 123]. Nanoparticles possess several advantages, including a high surface-to-volume ratio, significant carrier capacity, high stability, and the feasibility of scalable production [124]. Nanotechnology-based formulations have potential applications in disease prevention, diagnosis, treatment, therapeutic monitoring, and drug discovery [125]. Despite the improvements in convention anticancer therapies (e.g., chemotherapy, surgical resection and radiotherapy), the clinical outcomes are still unsatisfactory owing to the limited efficacy and serious adverse effects of these treatment modalities [126]. Nanotechnology is expected to address and surpass the shortcomings of current cancer therapies. Nanoparticles have been considered as one of the excellent tools for targeted drug delivery in a controlled manner [127]. Nano-based therapeutic systems promote drug stability, absorption and therapeutic concentration, and they have deep tissue penetration to augment the EPR effect, contributing to effective drug targeting and few side effects [128]. The targeting mechanisms of nanomedicine formulations can be generally grouped into two types, passive and active targeting [129]. In passive targeting mode, the accumulation of therapeutic nanoparticles into the tumor site is attributed to the characteristics of the tumor. Excessive proliferation of cancer cells leads to neovascularization. The new blood vessels have large pores in the vascular walls that facilitate passive targeting [130]. Due to rapid and defective angiogenesis, nanoparticles can diffuse from leaky blood vessels and eventually accumulate within the tumor site [131]. Moreover, poor lymphatic drainage enhances nanoparticle retention contributing to EPR effects on cancer cells [132]. In contrast, the high interstitial fluid pressure in the TME results in decreased uptake and heterogeneous distribution of drug nanocarriers [133]. Active targeting mechanism relies on specific ligands (e.g., folate, glycoproteins and transferrin), which interacts with surface receptors overexpressed in tumors [134]. This targeting is achieved by surface modification of drug-loading nanoparticles with specific ligands capable of binding to antigens/receptors in target cancer cells [135]. Nucleic acids, antibodies, peptides and proteins may be specific ligands grafted in the surface of nanocarriers [136]. Ligand-receptor interaction induces uptake and absorption of nanoparticles via receptor-mediated endocytosis [129]. Multiple factors, including nanoparticle size and structure, ligand density and ligand-receptor chemistry, affect the efficiency of active targeting scheme [137]. So far, several nanoformulations have been developed for clinical use in cancer treatment (Table 1).

Table 1 Clinically approved nanomedicines for cancer treatment

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Lipid-based nanoparticles

Lipid-based nanoparticles have the most typical configuration of a spherical system, containing at least one lipid bilayer surrounding an internal water chamber. Lipid-based nanoparticles show various advantages, such as simple formulation, biocompatibility, high bioavailability, self-assembly, and the capability to carry diverse payloads [138]. Therefore, lipid-based nanoparticles are one of the most common types of nanopharmaceuticals. Liposomes are a subtype of lipid-based nanoparticles that are still most frequently used to date [139]. Liposomes are capable of encapsulating and delivering hydrophilic, hydrophobic and lipophilic agents [140]. Liposomes carrying anticancer drugs for chemotherapy or immunotherapy can reduce non-specific adverse and toxic effects of these drugs on normal tissues [141]. The stability of liposome-based systems can be controlled by adjusting their size, composition, and surface charge and modifications [142]. Reportedly, surface modifications of liposomes can enhance the circulation time and promote drug delivery, which allow for drug accumulation in tumor tissues [143]. Currently, several liposomal pharmaceuticals have been approved for clinical cancer therapy. Caelyx, Doxil and Myocet were formulated to deliver doxorubicin (DOX) and are indicated for the treatment of ovarian cancer, myeloma and breast cancer, respectively [144,145,146]. These nanoformulations protect DOX from chemical and enzymatic degradation in the blood, and reduce drug-induced cardiotoxicity [147]. DaunoXome prepared by encapsulating daunorubicin in a non-PEGylated liposome is applicable for patients with human immunodeficiency virus (HIV)-associated Kaposi sarcoma [148]. Lipusu is a non-PEGylated liposome formulation carrying paclitaxel for the treatment of breast cancer, non-small cell lung cancer (NSCLC) and ovarian cancer [149]. Marqibo, a liposome preparation of vincristine, has been approved for the treatment of leukemia [150]. Mepact, a liposomal mifamurtide, is mainly used for the treatment of osteosarcoma [151]. Onivyde, a PEGylated liposomal irinotecan, is mainly administered for the treatment of metastatic pancreatic cancer [152]. Vyxeos is a formulation of cytarabine and daunorubicin in liposomes that has been granted for the treatment of acute myelogenous leukemia [153].

Polymeric nanoparticles

Polymeric nanoparticles, engineered nanostructured materials, have been widely applied in the field of drug delivery due to structural versatility for controlled drug release, high kinetic stability, possibilities for surface functionalization, and the ability to protect drug against the environment [154, 155]. According to their internal architectures, polymeric nanoparticles can be divided into nanospheres and nanocapsules [156]. Polymeric nanospheres consist of a solid polymeric matrix and commonly display a regular sphere structure, in which drugs are distributed throughout the matrix [157]. Polymeric nanocapsules are composed of an inner core containing therapeutic compounds and enveloped by a polymeric shell [158]. Polymeric nanoparticles can carry and deliver hydrophobic and hydrophilic substances, as well as substances with varied molecular weights [159]. Thus, polymeric nanoparticles may be a useful platform for joint delivery of different therapeutic drugs. Altering the characteristics (e.g., composition, stability, and surface charge) of polymeric nanoparticles can regulate their loading efficiency and release kinetics of payloads [160, 161]. Clinically approved polymeric nanoparticles include Eligard, Genexol-PM, Kadcyla, and Oncaspar. Eligard, a polymeric matrix formulation of leuprolide acetate, increases the efficiency and prolongs action duration of the loaded drug [162]. Moreover, this nanoformulation was approved for the treatment of advanced hormone-dependent prostate cancer. Genexol-PM, a polymeric micelle nanoparticle formulation of paclitaxel, has controlled drug release and is applicable for the treatment of breast cancer and pancreatic cancer [163]. Kadcyla, also called Ado-Trastuzumab emtansine or T-DM1, is a protein-based nanocompound consisting of the anti-HER2 antibody transtuzumab conjugated via a non-cleavable maleimidomethyl cyclohexane-1-carboxylate thioether linker to the cytotoxin DM1 [164]. Kadcyla selectively delivers DM1 to HER2-positive cancer cells, resulting in cancer cell death [165]. Moreover, trastuzumab also exerts an anticancer activity via blockade of HER2 signalling, and the binding of transtuzumab to HER-2 receptor also induces antibody-dependent cell-mediated cytotoxicity. Kadcyla is indicated for the adjuvant treatment of HER2-positive breast cancer [166]. Oncaspar, a PEGylated formulation of the enzyme asparaginase, inhibits tumor growth by decreasing the level of the amino acid asparagine in the blood [167]. This nanopharmaceutical extends half-life of encapsulated drugs and attenuates the risk of adverse reactions. Oncaspar has been approved for the treatment of acute lymphoblastic leukemia.

Protein-based nanoparticles

Protein-based nanopharmaceuticals can be formulated using proteins such as albumin, fibroin, gelatin, and lipoprotein [168]. Protein-based nanoparticles are used to carry anticancer drugs, genetic materials and growth factors. Protein nanoparticles exhibits many advantages, including high safety, favorable biocompatibility and biodegradability. Abraxane and Pazenir are albumin-bound paclitaxel nanoparticles for the treatment of metastatic breast cancer and NSCLC [169]. In terms of mechanism, these nanopharmaceuticals improve the tumor-targeting ability of paclitaxel and enhance antitumor T cell responses. Ontak represents a Denileukin diftitox (engineered fusion protein combining IL-2 with diphtheria toxin) nanoparticle that is administered to treat cutaneous T-cell lymphoma [170]. Ontak acts as an IL-2 receptor antagonist designed to direct the cell-killing effect of diphtheria toxin towards IL-2 receptor-overexpressing target cells [171].

Metallic-based nanoparticles

Iron oxide nanoparticles are made up of an iron oxide core that responds to clinical magnetic devices and coated with biocompatible molecules [172]. In vivo, iron oxide nanoparticles can be selectively heated by alternating magnetic fields, leading to the temperature-dependent liberation of drugs [173]. For instance, NanoTherm, an iron oxide nanoparticle with aminosilane coating, was approved for the treatment of glioblastoma multiforme (GBM) and prostate cancer [174].

Mechanisms of action of nanodrug delivery systems in improving immunotherapeutic efficacy

In recent years, nanoparticles have emerged as a new research hotspot in the field of oncology. Various nanostructures have been introduced as novel adjuvant approaches to enhance the efficacy of cancer immunotherapy (Table 2). Furthermore, nanoparticles can be equipped with diverse ligands (e.g., antibodies and aptamers), thereby promoting their interaction with target molecules, including surface receptors on cancer cells. Consequently, nanoparticles can be used as efficient targeting drug delivery systems that result in drug accumulation at therapeutic doses in tumors. Nanoparticles have a relatively high depth of tissue penetration to promote the EPR effect. In addition, manipulation of nanoparticle characteristics can optimize the release rate of loaded therapeutic drugs. Taken together, nanoparticles have the ability to improve drug bioavailability and decrease the dosing frequency, forming a solid basis for better cancer treatment.

Table 2 An overview of studies that evaluate feasibility and efficacy of nanomaterials in cancer immunotherapy

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Nanotechnology for immune checkpoint blockade therapy

Nanocarrier-mediated alteration of immune checkpoint molecules

Nanoparticles can be engineered to directly modify immune checkpoints on cancer cells or immune cells, inducing innate and adaptive immune responses (Fig. 3). For instance, a core–shell structure of an immunomodulating nanoparticle was formed by synthesizing and coating bovine serum albumin nanocapsule (nBSA)-phenylboronic acid (PBA)-immunoglobulin G (IgG) with glucose-modified poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(N-(3-aminopropyl)-methacrylamine) (PMPC-b-PApm/Glu) [175]. Once they enter tumor tissues, PMPC-b-PApm/Glu disassembled from the immunomodulating nanoparticle to release the bifunctional core nBSA-PBA-IgG. The glyco-immune negative checkpoint sialic acid (SA) expressed on the cancer cell surface competitively bound to PBA on nBSA-PBA-IgG, replacing the PMPC shell due to the strong binding affinity of SA to PBA. The discharged bifunctional core tightly coupled with cancer cells and presented IgG on the surface, contributing to the in situ modification of cancer cell surface with immune-activating signals (IgG). Subsequently, the recognition of the fragment crystallizable (Fc) region of IgG by the Fc receptor bearing on NK cell surface led to the activation of tumor-infiltrating NK cells, which induced the apoptosis of target cancer cells. Immunomodulating nanoparticles effectively activated NK cell-mediated immunity and showed marked anticancer efficacy in melanoma-bearing mice. The liposome system was used as a nanocarrier for the drug conjugate protoporphyrin IX (PpIX)-NLG919 (termed as PpIX-NLG@Lipo) [176]. PpIX-NLG@Lipo demonstrated a strong ability to generate reactive oxygen species (ROS) for the purpose of destroying breast cancer cells through photodynamic therapy (PDT). Moreover, PpIX-NLG@Lipo reduced the activity of the immune checkpoint indoleamine-2,3-dioxygenase (IDO), thereby enhancing PDT-induced immune responses. Consequently, this resulted in an increased infiltration of CD8⁺ T lymphocytes into the tumor site, ultimately leading to regression of both primary and distant tumors. Photosensitive polydopamine-coated nanoparticles co-loaded with the chemotherapeutic agent gemcitabine and the IDO inhibitor NLG919 (N/PGEM/dp) efficiently transferred the loaded agents to both primary and remote pancreatic cancer cells [177]. N/PGEM/dp promoted the infiltration of NK cells and tumor antigen-specific CTLs, as well as the release of cytokines (e.g., granzyme B (GzB) and IFN-γ) by these immune cells. As expected, N/PGEM/dp demonstrated a significant tumor inhibition effect in a murine pancreatic cancer model.

Nanocarrier-based systems incorporating small interfering RNAs (siRNAs) for silencing immunosuppressive immune checkpoints have a high efficiency of intracellular delivery of loaded siRNAs to the TME, resulting in more intense immune responses compared to antibody-based blockades (e.g., anti-PD-L1 antibody and anti-PD-1 antibody) [178]. Several siRNA-loading nanoplatforms have been reported for immune checkpoint silencing (Fig. 4). A silica nanocarrier loaded with PD-L1-targeting siRNAs efficiently delivered siRNAs into T cells, resulting in the downregulation of PD-L1 and promotion of T cell survival [179]. PD-L1 siRNA-loaded nanocarriers have the potential to improve the efficacy of adoptive T-cell immunotherapy in cancer patients. Likewise, acidic tumor extracellular pH-responsive nanoparticles encapsulated with a TGFβR inhibitor and PD-L1-specific siRNA stimulated CD8⁺ T cell-mediated antitumor immunity to retard PDAC growth [180]. Poly(lactic-co-glycolic-acid) (PLGA) nanoparticles carrying PD-L1 siRNA and PD-1 siRNA cooperated with PLGA nanoparticles encapsulating tumor antigen (ovalbumin (OVA) or E7 peptide) and adjuvant (poly I:C) showed synergistic antitumor effects against thymoma by eliciting CD8⁺ T cell-directed immune responses [178].

Combined treatment of nanotechnology and immune checkpoint inhibitors

It has been established that nano-immunotherapy can improve the therapeutic outcome of conventional ICIs. Accumulating evidence shows that the enhancing effects of nanocarriers on ICI efficacy are mainly attributable to their activity in promoting antigen presentation and stimulating CD8⁺ T cell immune responses. A natural nanopolymer poly(β-L-malic acid) (PMLA) with covalently conjugated anti-CTLA-4 and anti-PD-1 antibodies was capable of crossing the blood–brain barrier (BBB) to penetrate GBM cells [181]. PMLA-based immunoconjugates increased the populations of CD8⁺ T cells, macrophages, and NK cells and decreased the populations of Treg cells in the GBM tissue. Importantly, this combination of immunoconjugates possessed stronger anticancer effects than single ICI-bearing PMLA or free anti-CTLA-4 and anti-PD-1 antibodies in vivo. Trans-BBB transfer of tumor-targeted nanopolymer-conjugated ICIs may represent a valuable therapeutic strategy for GBM. Chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) synergistically acted with PD-1 blockade to suppress colon carcinoma development and prolong the survival of cancer-bearing mice [182]. This was achieved by increasing intratumoral T cell infiltration and enhancing the intratumoral ratio of CD8⁺ T cells to Treg cells. Cancer cell membrane (CCM)-coated PLGA/gambogic acid nanoparticles (CCM-PLGA/GA NPs) had a high tumor-targeting ability and functioned to promote DC maturation [183]. The combination of CCM-PLGA/GA NPs with anti-PD-1 treatment significantly inhibited colon carcinoma growth in vivo. A ROS-sensitive nanocarrier, ^TKHNP-C/D, was developed to carry two immunogenic cell death (ICD)-inducing agents, chlorin e6 (Ce6) and DOX [184]. ^TKHNP-C/D-based therapy efficiently synergized with anti-PD-1 treatment to exert an abscopal effect, which repressed primary mammary tumor growth and restricted metastatic spread. Macrophage membrane-coated nanoparticles loaded with a TGFβR1 kinase inhibitor (Mϕ-SDNP), combined with anti-PD-1 antibodies, had a significantly strong antitumor effect in breast cancer-bearing mice [185].

A nanoparticle loaded with siRNAs targeting zinc finger Asp-His-His-Cys-type palmitoyltransferase 9 (NP-siZDHHC9) enhanced infiltration and activation of CD8⁺ T cells while reducing infiltration of myeloid-derived suppressor cells (MDSCs) [186]. It also increased production of proinflammatory cytokines and chemokines (e.g., IFN-γ, IL-2, and tumor necrosis factor-α (TNF-α)). NP-siZDHHC9 combined with anti-PD-L1 treatment efficiently inhibited pancreatic cancer development and prolonged the survival of tumor-bearing mice by transforming the immunosuppressive TME into a proinflammatory state. DC-targeted nanoparticles comprising Toll-like receptor 4/7/8 (TLR4/7/8) agonists were able to increase cytokine production, promote DC maturation and enhance the population of antigen-specific CD8⁺ T cells [187]. The DC-targeted nanoparticles synergized with anti-PD-1 therapy to suppress T-cell lymphoma progression. Nanoparticles (CNPs) incorporating a TLR9 agonist, cytosine phosphate guanine (CpG)-oligodeoxynucleotide (ODN), enhanced the therapeutic activity of the anti-PD-1 antibody in melanoma-bearing mice [188]. Pathogen-mimicking magnetite nanoparticles efficiently elicited antigen-specific CTL effector and memory responses [189]. The nanovaccine system in conjunction with PD-L1 inhibition conferred 100% long-term immune protection against various melanoma challenges. This nanovaccine combined with checkpoint blockade of PD-L1 may be a suitable option to improve TLR4 agonist-based immunotherapy in cancer. Surgically derived CCM-coated imiquimod (R837)-loaded poly(2-oxazoline) nanoparticles (SCNP/R837) efficiently migrated to the DLN and were absorbed and presented by plasmacytoid DCs (pDCs) to induce attraction and activation of NK cells and CTLs at tumor sites [190]. The nanoformulation remarkably retarded the progression of prostate cancer and extended animal survival. When combined with anti-PD-1, SCNP/R837 demonstrated improved therapeutic efficacy in mice bearing prostate cancer. The inflammasome-activating nanovaccine platform elicited antigen-specific CD8⁺ T cell responses characterized by increased production of GzB and IFN-γ [191]. This nanovaccine, along with ICIs (anti-CTLA-4 and anti-PD-L1 antibodies), effectively decreased tumor burden and extended animal survival in murine lymphoma, melanoma and colon carcinoma models.

In the past decades, ICIs have emerged as a powerful treatment modality in the field of cancer immunotherapy. However, ICIs are associated with immune-related toxicities that dampen their clinical activity. Applying nanotechnology to deliver ICIs may be a feasible solution to address critical issues in ICI treatments. The advantages of utilizing nanotechnology rely on the prominent features of nanoparticles, including formulation simplicity, biocompatibility, self-assembly, high bioavailability, practical accommodation of nanoparticle size, highly adjustable surface/morphological properties, and the ability to carry specific payloads [127, 284]. In vivo studies have demonstrated that nanoparticles preferentially accumulate within tumors due to their leaky vascular system and poor lymphatic drainage [285]. Nanoformulations can be designed as rational systems for controlled release of ICIs in response to diverse stimuli within the TME. Combination treatment of ICIs and nanotechnology overcomes tumor immune tolerance and enhances systemic antitumor immunity, which may benefit patients with poorly immunogenic tumors [286]. Further research efforts are required to establish the most effective protocols for integrating nanomaterials into ICI immunotherapies, including administration route, time and intervals, as well as potential off-target effects and adverse reactions. More accessible animal models must be developed to evaluate the effects of nanoparticle-based ICI therapy. Another area that warrants urgent attention is the elucidation of the pharmacokinetic property and systemic toxicity of nanoparticles. A better understanding of tumor immunology will contribute to optimizing the effectiveness of nanoparticle-based immune checkpoint therapies, ultimately boosting the likelihood of their successful translation into clinical practice.

Nanotechnology for adoptive cell therapy

Innate immune cell-based immunotherapy

TLR7/8 agonist-loaded nanoparticles selectively transported TLR7/8 mixed agonists to the endosome/lysosome of DCs [192] (Fig. 5). The nanoparticle-induced TLR7/8 activation favored the secretion of proinflammatory cytokines (IFN-γ, IL-12 and IL-18) and increased the expression of costimulatory molecules (CD40, CD70, CD80 and CD86) by DCs, both of which resulted in NK cell hyperactivation and degranulation. These immunostimulatory molecules further induced T cell-mediated immune responses. Furthermore, TLR7/8 agonist-loaded nanoparticles dramatically potentiated the therapeutic efficacy of monoclonal antibodies targeting epidermal growth factor receptor (EGFR) and HER2 in lung adenocarcinoma-bearing mice. Chiral nanoparticles facilitated the activation of NK cells and CD8⁺ T cells by mobilizing DCs [193]. Chiral nanoparticles induced the apoptosis of lymphoma cells and extended the survival of tumor-bearing mice. Liposome-anchored macrophages armed with TLR7/8 agonist (LAMΦ-m7/8a) maintained an antitumor M1 phenotype and exerted killing effects on cancer cells [194]. Moreover, LAMΦ-m7/8a enhanced the infiltration of antigen-specific CD8⁺ T cells and attenuated the population of MDSCs. LAMΦ-m7/8a in combination with DOX-loaded liposomes exhibited effective anticancer efficacy against breast cancer in vivo. LAMΦ-m7/8a may provide an appropriate alternative to adoptive cell-based therapy. The non-viral lipid nanoparticle (LNP)-based delivery system encapsulating siRNAs against intrinsic inhibitory NK cell molecules (SHP-1 and Cbls) efficiently unleashed NK cell activity to kill B cell lymphoma cells in vivo [195]. Treatment with cationic nanoparticle (cNP) enhanced the cytotoxic activity of NK cells by stimulating the expression of C-C motif chemokine receptor 4 (CCR4) and C-X-C motif chemokine receptor 4 (CXCR4) and promoting their interaction with triple-negative breast cancer (TNBC) cells [196]. cNP-activated NK cells demonstrated superior ability to suppress TNBC growth in vivo compared to control NK cells. The cNP-mediated activation of NK cells holds promise for NK cell-based cancer immunotherapy.

T cell-based immunotherapy

Polymeric nanoparticles carrying leukemia-specific CARs selectively modified circulating T cells [197]. Nanoparticle-edited CAR-T cells induced leukemia regression with efficacies comparable to adoptive T cell therapy in preclinical models. Plasmid DNA-loaded self-assembled nanoparticles (pDNA@SNPs^G1/800) efficiently shuttled the EGFR variant III (EGFRvIII) CAR-expression plasmid vector (pEGFRvIII CAR) into T cells, thus resulting in transient expression of EGFRvIII CAR in transfected T cells [198]. The presence of EGFRvIII CAR on T cell surface empowered T cells to recognize and kill EGFRvIII-positive cancer cells. pDNA@SNPs^G1/800 can be useful in engineering CARs in T cells and may hold considerable potential for CAR-T cancer immunotherapy. Nanogel-mediated delivery of IL-15 super-agonist (IL-15SA) complexes facilitated the expansion of T cells infiltrating the tumor tissue and contributed to CAR-T cell-mediated melanoma regression in vivo [199]. Incubation of T cells with immunoliposomes encapsulating a TGF-β inhibitor and a T cell targeting receptor CD45 or CD90 induced the expansion of granzyme-expressing T cells in vitro [200]. Upon adoptive transfer, T cells incubated with CD90-loaded immunoliposomes triggered strong T cell-mediated antitumor immune responses and suppressed melanoma growth in preclinical models.

Adoptive cell therapy is a promising approach for treating cancer, as evidenced by numerous clinical trials in hematologic and solid tumors. Despite its great potential in cancer intervention, the efficacy of adoptive cell therapy remains limited, particularly in the context of solid malignancies. In addition to restrictive anatomical barriers that hinder adequate delivery of T cells, the aberrant vasculature of solid tumors prevents T cell infiltration into the TME, thereby diminishing their local bioavailability and functionality. The immunosuppressive TME of solid tumors further blunts the antitumor effect of T cells. Nanocarriers offer a means to penetrate anatomical barriers and deliver therapeutic cargos to the target site. Thus, nanotechnology holds immense potential for improving adoptive cell therapy (Fig. 3). However, multiple hurdles remain for the clinical utility of nanoparticles in adoptive cell therapy. The effects of nanoparticle size, composition, structure and surface charge on T cell activity must be thoroughly determined. In vivo tracking and visualization technologies are critically required to explore how adoptively transferred T cells enter target cells, expand, and exhaust. It is necessary to develop improved targeting approaches, such as multi-ligand modifications, to ensure specific uptake and low toxicity. The density and patterns of surface modifications and nanomaterial surface topology should be assessed to optimize nanocarrier synthesis for immune cell binding and activation [287]. Strategies that favor controlled drug release from nanocarriers need to be employed in nanotechnology-assisted adoptive cell therapy. Nanoparticles act as a versatile delivery system that can transfer antibodies, genes and small molecules. However, the appropriate cargos that act synergistically with existing adoptive cell therapies remain to be established. A significant challenge in adoptive cell therapy lies in the lack of precise control over T cell behavior in vivo. Innovative technologies must be employed to achieve remote regulation of T cell function in vivo [288]. Before applying nanotechnology to adoptive cell therapy, the anticancer effect of nanoparticle-enhanced T cells must be validated in further clinical studies.

Nanotechnology for antibody-based targeted therapy

Radiosensitive gold nanoparticles were used to deliver tumor-targeting antibodies (Cetuximab) into the brain [201] (Fig. 6). Furthermore, Cetuximab-loaded nanoparticles specifically accumulated within the glioblastoma tissues. This nanoparticle-based therapy combined with standard of care treatment, comprising temozolomide (TMZ) and adjuvant radiotherapy, resulted in a significant inhibition of glioblastoma growth in vivo. The anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, DTA-1, is capable of abrogating tumor immunosuppression by transforming Treg cells into Th1 cells [289]. Catalase (CAT) and DTA-1 were loaded onto polydopamine (PDA)-indocyanine green (ICG) nanoparticles, generating a versatile nanoplatform, abbreviated as PDA-ICG@CAT-DTA-1 [202]. PDA-ICG@CAT-DTA-1 reversed tumor immunosuppression by decreasing the population of intratumoral forkhead box P3 (FOXP3)⁺ Treg cells and increasing the population of CD4⁺ effector T cells. In vivo, PDA-ICG@CAT-DTA-1 exerted growth inhibition effects on primary and distant breast tumors. An anti-IgG antibody (αFc) was conjugated to the surface of a nanocarrier to create an antibody immobilization platform (αFc-NP) [203]. αFc-NP effectively immobilized the anti-colony-stimulating factor 1 receptor antibody (αCSF1R) and the anti-CD47 antibody (αCD47) to form immunomodulating nanoformulations (imNAs). The imNAs facilitated the elimination of cancer cells by macrophages and induced the expansion of cancer-specific T cells. In a murine model of melanoma, intratumoral injection of imNAs resulted in more significant antitumor effects than the combination of αCSF1R- and αCD47-loaded nanoparticles. Anti-CD28 antibody-conjugated CCM nanoparticle (CCM-MPLA-aCD28), along with the adjuvant monophosphoryl lipid A (MPLA) incorporated into the nanoparticle, activated tumor-specific CD8⁺ T cells and demonstrated remarkable therapeutic efficacy in mice bearing colon cancer [204]. LNPs efficiently delivered the mRNA that encoded a commercial PD-1 antibody pembrolizumab [205]. Furthermore, pembrolizumab mRNA-encapsulated LNPs reduced colon cancer growth and prolonged animal survival by inducing both CD4⁺ and CD8⁺ T cell-mediated immune responses.

Emerging evidence indicates that nanoplatforms with customized functionalities improve the therapeutic outcomes of antibody-based therapies (Fig. 3). The vaccine adjuvant MPLA-loaded iron oxide nanoparticle (FH-MPLA) induced macrophage transition into an antitumor M1 phenotype [206]. In the immunotherapy-resistant model of murine melanoma, FH-MPLA combined with anti-CD40 (α-CD40) monoclonal antibodies resulted in cancer necrosis and regression. FH-MPLA may represent an adjunctive therapy to existing antibody-based cancer immunotherapy. Trastuzumab is the first monoclonal antibody approved for treating HER2-postive breast cancer [290]. However, resistance to trastuzumab treatment remains a significant hurdle that limits its therapeutic efficacy. A previous study revealed that TME PH-responsive nanoparticles effectively responded to the acidic niche, promoting the uptake of phosphatase and tensin homologue (PTEN) mRNA by breast cancer cells [207]. Once internalized, the loaded mRNAs were released to increase PTEN expression, leading to the inactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade and reversing trastuzumab resistance in breast cancer cells. Consequently, the combination of PTEN mRNA-loaded nanoparticles with trastuzumab resulted in a dramatic inhibition of tumor growth in an orthotopic mouse model of trastuzumab-resistant breast cancer.

Despite the advantages of antibody-incorporated nanomedicines, their anticancer activity merits further verification in clinical studies. Moreover, the limitations of antibody-based nanoparticles include high production costs and absence of suitable antibody conjugation methods. More cancer-associated targets that are appropriate for the development of antibody-incorporated nanomedicines should be identified. It is also important to assess the tumor penetration ability of targeting nanocarriers. The functionalization of nanomaterials with targeting ligands may impair their stealth properties, ultimately accelerating the in vivo clearance of nanoparticles by the host [291]. Integration of targeting ligands into nanoparticles may curtail their penetration and diffusion capacities in vivo by increasing the size of nanoparticles. Antibody-modified nanoparticles may not necessarily have enhanced tumor accumulation due to the complexity of in vivo environment [292]. To realize the clinical translation of antibody-incorporated nanoparticles, their features including pharmacokinetics, biodistribution, stability, and toxicity must be optimized [293]. This necessitates a thorough evaluation of various factors of nanoparticles, such as particle size, type of antibody, ligand density and conjugation strategy.

Nanotechnology for cancer vaccines

Cancer vaccines represent a promising cancer immunotherapeutic approach. Nanomedicines hold tremendous potential to increase vaccine effectiveness as they offer several advantages (e.g., nanoscale size, high stability and controlled antigen presentation) [294]. Particularly, nanocarriers can deliver molecule vaccines to the target lymphoid tissues or immune cells, which increases the effect and durability of antitumor immunity with minimum side effects and toxicity [295]. Due to their roomy cores or large surface areas, nanoplatforms can load multivalent antigens and/or adjuvant molecules, thus improving the immunogenicity of vaccines and intensifying antigen-specific adaptive immunity for cancer treatment. Nanovaccines consist of three main components: antigens, nanocarriers, and adjuvants. Nanosystems serve as a crucial bridge for efficiently delivering antigens to the TME, thus inducing effective immune responses. Antigens encapsulated in nanomaterials can be in the form of tumor cell lysates, peptides, and mRNAs encoding tumor antigens [296, 297] (Fig. 7). The therapeutic mechanisms of cancer vaccines involve expanding the repertoire of antitumor cells and reducing tumor immunosuppression [298, 299].

Tumor lysate nanovaccines

Nanovaccines that deliver tumor cell lysates not only increase the repertoire of tumor-derived antigens as immune targets but also induce ICD to enhance antitumor immunity [296]. Tumor cell-based nanovaccines will open the door to individualized cancer vaccination and immunotherapy. Currently, several nanoplatforms loaded with tumor cell lysates have been fabricated. For instance, lipid zinc phosphate hybrid nanoparticles (LZnP NPs) were used to deliver a TLR4 agonist and melanoma cell-derived tumor lysate (TLS) for vaccination [208]. TLS-loaded LZnP NPs were able to induce DC maturation and CTL response. The TLS-loaded LZnP nanovaccine, in collaboration with the immune checkpoint antagonist d-peptide antagonist (^DPPA-1), exerted antitumor effects in both prophylactic and therapeutic melanoma models. Magnetic liposomes containing melanoma lysate (Ag-MLs) significantly accumulated in lymph nodes and increased the infiltration of DCs and CTLs into the tumor, which correlated with effective anticancer efficacy in a murine melanoma model [209]. PH-sensitive nanovaccines encapsulating cancer cell lysates and immune adjuvant CpG altered the acidic TME, contributing to the activation of CTLs and inhibition of breast cancer development in vivo [210]. Engineered Salmonella (EnS) was wrapped with tumor cell lysate-coated PDA nanoparticles to produce the cancer vaccine EnS@PDA@CL [211]. EnS@PDA@CL was able to deliver autologous antigen-containing nanoparticles to tumor hypoxia regions through the circulation. The particles induced antitumor immunity by activating DCs and increasing the infiltration of CTLs. Therefore, EnS@PDA@CL delayed pancreatic cancer progression in vivo.

Tumor antigen-loaded nanoparticles

Encapsulation of cancer antigens within diverse nanomaterials significantly enhances their persistence in the circulation, lymphoid tissues, or APCs. It is increasingly recognized that extending the persistence of cancer antigens increases their immunogenicity, and a number of nanovaccines have been investigated to achieve this objective. For instance, Ti₃C₂ MXene-based nanoplatforms (MXP) codelivering OVA and a TLR9 agonist (CpG-ODN) enhanced DC activation and induced CTL immune responses [212]. MXP-based immunotherapy and photothermal therapy efficiently eliminated melanoma in vivo. OVA-loaded porous silica nanoparticles (PSNs) recruited APCs and elicited sustained T cell activation [213]. OVA-loaded PSNs also triggered strong antigen-specific antibody responses compared to OVA alone. OVA-loaded PSNs elicited melanoma regression in both prophylactic and therapeutic vaccination. Polyethylene glycol (PEG)-lipid polyester nanoparticles (PEG BR647-NPs) incorporating OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were taken up by tumor-associated DCs (TADCs) [214]. Following this, OVA and STAT3 siRNA were released into the cytoplasm, where OVA was presented by MHC-I to activate T cells, and STAT3 siRNA promoted TADC maturation to induce antitumor T cell immunity. PEG BR647-NPs also reversed the immunosuppressive TME by depleting MDSCs and Treg cells. Collectively, PEG BR647-NP-based nanovaccines remodeled the TME and thus induced antitumor effects in melanoma-bearing mice. Magnetic nanoparticle modified with the OVA_254–267 antigen and CpG (MNP-CpG-COVA) promoted DC activation and induced systemic tumor-specific effector CD8⁺ T cell responses [215]. Therefore, MNP-CpG-COVA treatment slowed down melanoma growth and prolonged mouse survival in vivo. Graphene oxide nanosheet (nsGO) loaded with OVA and the adjuvant Poria cocos polysaccharides (PCP) was effectively captured by DCs, which induced the activation of DCs [216]. Accordingly, nsGO/PCP/OVA nanocarriers triggered robust OVA-specific Th1 and Th2 immune responses. Vaccination with nsGO/PCP/OVA nanoformulations dramatically inhibited lymphoma growth in both prophylactic and therapeutic tumor models. Self-assembled vaccines based on cancer-specific antigen peptide (MAGE-A1 peptide) and a TLR2 agonist showed an increased ability to induce DC maturation and CD8⁺ T cell activation, leading to the inhibition of tumor growth in a murine breast cancer model [217]. Chitosan nanoparticles encapsulating recombinant CD44v (rCD44v) antigen efficiently elicited specific antibody responses and increased the production of IFN-γ and IL-17 by splenocytes [218]. As a result, rCD44v-loaded nanoparticles not only suppressed breast cancer growth but also reduced metastatic burdens in a murine model.

Peptide nanovaccines

Peptide vaccines incorporate key amino acid sequences of tumor antigens, which trigger CTL antitumor immune responses and alleviate cancer immunosuppression [300]. LNP-based vaccines, which displayed fibroblast activation protein α-specific epitope peptides (FAP_PEP), resulted in significant growth inhibition of desmoplastic tumors by eliminating FAP⁺ cancer-associated fibroblasts (CAFs) and inhibiting extracellular matrix (ECM) generation in the TME [219]. The combinatorial therapy of FAP_PEP-displaying nanovaccines and the chemotherapeutic agent DOX increased drug accumulation within the tumor and led to synergistic anticancer effects that were far better than each monotherapy. Antimicrobial peptide FK-13-loaded nanoparticles (8FNs) reversed the immunosuppressive TME and induced antitumor CD8⁺ T cell responses [220]. Thus, 8FNs exhibited marked prophylactic and therapeutic efficacy against melanoma growth, suppressed cancer cell metastasis and extended the survival of tumor-bearing mice. DNA-coupled nitrate T helper cell epitope nanoparticle (DCNP) induced the activation of neoantigen-specific CD8⁺ T cells that inhibited melanoma growth in vivo [221]. Su et al. [222] developed pH-responsive polymeric micellular nanoparticles to deliver TLR7/8/9 agonists and peptide neoantigens to DLNs for efficient antigen presentation. These nanoparticles increased the immunogenicity of peptide neoantigens, induced strong antitumor T cell immunity, and limited tumor immunosuppression. As expected, the nanovaccine, especially when combined with anti-PD-1 antibody, exerted a significant therapeutic effect in murine models of CRC and GBM.

TLR agonist-conjugated antigen nanoparticles

Redox-responsive antigen nanoparticles conjugated with TLR7/8 agonists induced CTL immune responses and long-term immunological effects [223]. The prophylactic and therapeutic anticancer effects of this nanovaccine were established through in vivo murine lymphoma models. Likewise, TLR7/8 agonist resiquimod (R848)-loaded acid-responsive liposome-coated PDA nanoparticles selectively targeted DCs and released R848 for efficient antigen presentation [224]. PDA nanoparticles prevented the metastasis and recurrence of breast cancer. The therapeutic vaccine comprising high-mobility group nucleosome-binding protein 1 (HMGN1), R848 and anti-PD-L1-loaded ROS-responsive mesoporous silica nanoparticle (MSN@TheraVac) was previously developed for the treatment of colon cancer [225]. MSN@TheraVac promoted the maturation of DCs by increasing the surface expression of CD80, CD86 and CD103 and facilitating the production of proinflammatory cytokines (e.g., IL-1β, IL-12 and TNF-α). MSN@TheraVac treatment resulted in complete tumor regression and elicited tumor-specific protective memory responses in colon cancer-bearing mice. This therapeutic vaccine holds potential for being translated into a clinical treatment option for colon cancer patients.

A TLR9 agonist (CpG)-coated tumor antigen-encapsulated nanoparticle-based vaccine decreased lung colonization by breast cancer cells through the induction of humoral and cellular immune responses [226]. Moreover, the nanovaccine enhanced tumor-specific generation of GzB and IFN-γ by lung-derived CD8⁺ T cells. In addition, intranasal delivery of CpG-coated nanoparticles promoted the accumulation of tumor-specific lung resident memory T cells in the lungs of breast cancer-bearing mice. This nanovaccine may be used as a prophylactic measure to prevent the pulmonary metastasis of existing tumors. Shi et al. [227] designed and constructed a therapeutic nanovaccine, Alum-CpG@Fe-Shikonin NPs, which consisted of CpG-ODN-loaded aluminum hydroxyphosphate nanoparticle covered by Fe-Shikonin metal-phenolic networks (MPNs). Upon internalization by breast cancer cells, the shell of Fe-Shikonin MPNs disassembled into Fe²⁺ and Shikonin, triggering ferroptosis and necroptosis in cancer cells. Autologous cancer cell lysates were taken up by Alum NPs and codelivered with CpG-ODN to APCs to stimulate antitumor immune responses. Alum-CpG@Fe-Shikonin NPs selectively eliminated primary breast cancer and exhibited a robust abscopal effect on suppressing distant tumors. Importantly, they also induced a persistent antigen-specific immune memory effect to prevent cancer cell metastasis and recurrence. Self-assembled CpG nanoparticles modified the TME by favoring the production of proinflammatory cytokines, promoting the conversion of macrophages from an immunosuppressive M2 type to an immunoactivated M1 type, and inducing T cell activation [228]. CpG nanoparticles with a pompon-shaped nanostructure synergistically acted with OVA to suppress melanoma growth in vivo. This study indicates that CpG nanoparticles hold great promise as a prospective immunological adjuvant in cancer immunotherapy. Cyclodextrin-based polymer nanoparticles (CDPN) encapsulating two epitope peptides (the TLR7/8 agonist R848 and the TLR9 agonist CpG) had increased cancer targeting capability [229]. This nanovaccine significantly promoted antigen capture and cross-presentation by APCs, thus exerting antagonistic effects against different tumors in preclinical models.

Viral nanovaccines

Considering the association between viral infection and carcinogenesis, viral antigens provide an important resource for the development of cancer nanovaccines. Nanoparticles bearing a peptide (8Qm) derived from the HPV E7 protein conjugated to polyleucine markedly repressed cervical cancer growth and prolonged mouse survival [230]. Mechanistic investigation showed that nanoparticle-mediated delivery of the 8Qm conjugate stimulated CD8⁺ CTLs and enhanced IFN-γ production. Muramyl dipeptide (MDP) and HPV E7 peptide, encapsulated by PLGA nanoparticles along with an immune agonist β-glucan, efficiently eliminated cervical cancer in a murine model by promoting tumor-specific effector adaptive immune responses [231]. The PLGA nanoparticles provide a promising delivery platform for the design and development of cancer nanovaccines. LNP-encapsulated mRNA vaccines encoded a chimeric protein derived from the fusion of the HSV-1 glycoprotein D and the HPV E7 oncoprotein (gDE7) [232]. These vaccines showed potential therapeutic efficacy in cervical cancer-bearing mice by activating E7-specific CD8⁺ T cells. The gDE7 mRNA-LNP vaccines also induced memory T cell responses, which prevented tumor relapses. LNP loaded with mRNA encoding the HPV E7 protein, referred to as HPV mRNA-LNP, stimulated CD8⁺ T cells and improved their functionality [233]. The combined treatment of HPV mRNA-LNP and anti-LAG3/anti-CTLA4 enhanced HPV-specific CD8⁺ T cell immune responses and prevented the growth of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Chitosan-coated PLGA nanoparticles encapsulating HPV16 E7_44–62 peptides were decorated with cellular membrane derived from cancer cells undergoing ICD [234]. The PLGA nanoparticles promoted DC maturation and facilitated the accumulation of tumor antigens in lymph nodes. Immunization with this nanovaccine contributed to in vivo tumor inhibition in thyroid cancer-bearing mice. Spike nanoparticles delivered a hepatocellular carcinoma (HCC)-specific neoantigen and a TLR9 agonist (ODN-1826) to DCs, inducing CD8⁺ T cell responses that retarded HCC in vivo growth and inhibited lung metastasis [235]. Polymeric nanoparticles encapsulating the HCC neoantigen preferentially accumulated in the spleen, facilitating neoantigen expression by APCs [236]. This led to the induction of robust antigen-specific T cell immunity and inhibition of HCC development in vivo. Furthermore, the personalized neoantigen vaccine combined with anti-PD-1 resulted in complete tumor regression and induced long-term tumor-specific immune memory, which inhibited cancer recurrence and metastasis. LMP2-mRNA LNP (C2@mLMP2) promoted the expansion of CD8⁺ memory T cells [237]. C2@mLMP2 improved the anticancer efficacy of anti-PD-1 therapy in mice with Epstein-Barr virus (EBV)-related tumors. These findings provided theoretical evidence for future clinical studies that could extend the application scenarios and effectiveness of nano-immunotherapy in EBV-related tumors.

mRNA nanovaccines

mRNA-based approaches show therapeutic potency in cancer immunotherapy. To achieve optimal therapeutic outcomes, mRNA molecules must precisely reach target cells and produce desired proteins [301]. Since targeted mRNA delivery and endosomal evasion pose significant challenges, it is of great importance to develop safe and efficient delivery vehicles. A number of nanomedicine delivery platforms, such as polymeric nanoparticles and LNPs, have been fabricated for therapeutic mRNA delivery [302]. Among these, LNPs are the most widely used mRNA delivery system [303]. LNPs have various advantages over other delivery vehicles, including excellent biodegradability, superior safety, high encapsulation efficiency, rapid, cost-effective and mass production, low toxicity, and inherent ability to induce immune responses [304]. LNPs act as a versatile delivery system that ensures mRNA stability, improves cellular uptake, and fosters cytoplasmic release upon internalization [305]. Due to these unique properties, LNPs have attracted considerable attention as an optimal choice for delivering therapeutic mRNA vaccines.

The therapeutic potential of several mRNA nanovaccines has been evaluated in preclinical studies. A ROS-responsive polymeric nanoparticle platform was generated for co-delivery of p53 mRNA and the photosensitizer ICG [238]. The disassembly of nanoparticles induced by ROS enhanced the translation of p53 mRNA, thereby facilitating apoptosis of lung cancer cells. In a preclinical model, the co-delivery of p53 mRNA and ICG mediated by nanoparticles showed anticancer effects against lung cancer. PHTA-based polymeric nanoparticles facilitated effective migration of OVA-encoding mRNA (mOVA) to lymph nodes and allowed persistent protein translation in vivo [239]. mOVA-loaded PHTA-based polymeric nanoparticle (PHTA-C8/mOVA) favored DC maturation and induced strong CD8⁺ T cell-mediated antitumor immunity. PHTA-C8/mOVA also reduced the growth of melanoma in tumor-bearing mice. mOVA-loaded LNPs suppressed melanoma growth and prolonged mouse survival by inducing Th1 and Th2 immune responses in both prophylactic and therapeutic vaccination models [240]. Moreover, mOVA-loaded LNPs combined with an anti-CTLA-4 antibody showed enhanced anticancer efficacy in vivo. Engineered nanoparticles codelivering mOVA and CpG induced antigen-specific CD8⁺ T cell responses and exhibited efficient anticancer efficacy in vivo models of murine colon adenocarcinoma and melanoma [241]. Another study showed that LNP-based vaccines containing mOVA activated CD8⁺ T cell responses and exhibited significant anti-carcinogenic effects against lymphoma in vivo [242]. Tripalmitoyl-S-glyceryl cysteine bound to a pentapeptide (PAM3CSK4, Pam3) was incorporated as an adjuvant within OVA mRNA-LNPs [243]. Pam3-incorporated LNPs effectively induced antigen-specific CD8⁺ T cell immune responses, and prevented tumor growth in lymphoma-bearing mice. LNPs entrapped a modified mRNA encoding for a bacterial toxin (pseudomonas exotoxin A), inducing anticancer effects and prolonging overall survival (OS) of melanoma-bearing mice [244]. Three LNP-encapsulated mRNA vaccines encoding a chimeric protein fused by HSV-1 glycoprotein D and HPV-16 E7 oncoprotein (gDE7) were fabricated [232]. gDE7 mRNA-LNP vaccines induced memory T cell responses that restrained the recurrence of HPV-associated tumors and inhibited subcutaneous tumors in mice. LNP encapsulating rituximab-encoding mRNA dramatically eradicated lymphoma cell growth and extended animals’ survival [245]. IL-2-mRNA-LNP induced robust antitumor immunity and showed therapeutic efficacy in melanoma-bearing mice [246].

Recent years have witnessed the rapid development of mRNA-LNP technology, which opens up a new avenue for cancer treatment. The composition and structure of lipids markedly affect the physical properties of LNPs, including particle size and surface characteristics [303]. Accordingly, the safety, efficacy and drug distribution of LNPs can be optimized by modulating their lipid composition. Given that cationic lipids are a key factor determining the delivery efficiency of mRNA-LNP formulations, cellular uptake and endosomal escape of LNPs can be improved by regulating lipid head groups and hydrophobic tails. Furthermore, tissue/cell-specific delivery may be achieved by tuning the lipid structure of LNPs. To maintain the therapeutic efficacy, repeated injections of mRNA-LNPs are necessary, which may induce unwanted immune responses. This in turn attenuates the efficacy of mRNA-LNP therapy. Strategies that aim at prolonging mRNA expression or identification of cancer type-specific mRNAs can be possible solutions. mRNA cancer vaccines have immense potential for precision cancer therapy [306]. Heterogeneity is a fundamental principle in designing personalized cancer vaccines, which can prevent tumor immune evasion and improve the efficacy of cancer vaccines [307]. Personalized cancer vaccines targeting a broad spectrum of epitopes expressed across distinct tumor regions can induce diversified antitumor immune responses to overcome clonal evolution and the consequent tumor heterogeneity [308]. However, this strategy burdens cancer vaccine development, and increases the cost and timing of vaccine manufacturing [96]. Artificial intelligence (AI)-powered technologies, including quantification of mutated transcript abundance, prediction of MHC-binding affinity, and clonality of mutations to identify neoantigens based on tumor genomic data, may significantly enhance the precision and efficiency of vaccine design processes. At present, AI-driven mRNA vaccine development remains underexplored, and it constitutes a vital and compelling area for future in-depth investigations.

Nanotechnology for oncolytic virotherapy

Oncolytic virus-based cancer vaccines have emerged as a promising approach in the field of cancer immunotherapy. Oncolytic adenoviral vector (Ad) nanospheres targeted and attacked lung cancer cells partially by triggering T cell immune responses [247]. Oncolytic Ad nanospheres may be used as a multifunctional drug delivery platform for virotherapy. Oncolytic adenovirus nanovesicles combined with anti-PD-1 antibody showed anticancer efficacy and prolonged animals’ survival in a murine melanoma xenograft model [248]. Mechanistic investigation indicated that this combination treatment promoted the intratumoral infiltration of CD4⁺ and CD8⁺ T cells and facilitated the production of TNF-α and IFN-γ. Combined immunotherapy of oncolytic virus nanovesicles and ICIs has the potential be translated into clinical applications for cancer patients. ExtraCRAd was a nanoparticle platform consisting of an oncolytic adenovirus artificially coated with cancer membranes carrying cancer-specific antigens [249]. ExtraCRAd exhibited enhanced infectivity and oncolytic activity. This nanoparticle system inhibited the growth of melanoma and lung cancer by inducing robust CD8⁺ T cell immune responses in both murine prophylactic and therapeutic models. The oncolytic adenovirus AdNuPARmE1A was coated with PEGylated oligopeptide-modified poly(β-amino ester)s (OM-pBAEs) to generate nanoparticle formulations [250]. The nanoparticles protected the oncolytic viruses from elimination by neutralizing antibodies. Systemic administration of OM-pBAEs showed increased oncolytic capability and efficiently reduced PDAC growth in vivo.

LNP-encapsulated synthetic Seneca Valley virus (SVV) promoted the recruitment of CD8⁺ T cells and led to dramatic inhibition of tumor growth in a murine xenograft model of small cell lung cancer (SCLC) [251]. Intravenous administration of synthetic SVV formulated with LNPs was well tolerated and increased the anticancer activity of PD-1 blockade in mice bearing neuroblastoma. Coassembling HSV with biocompatible magnetic nanoparticles improved tumor targeting ability and protected the virus from clearance by neutralizing antibodies [309]. The nanoparticles increased the intratumoral infiltration of CD8⁺ T cells and enhanced antitumor immunity, thereby causing breast cancer regression and extending animal survival in a murine model. Engineered nanoparticles derived from Norovirus (Nov-S-Catcher003) promoted the maturation of bone marrow-derived DCs and induced strong tumor-specific T cell immune responses [253]. Immunization with Nov-S-Catcher003 prevented the growth of cervical cancer in vivo. The engineered Norovirus-derived delivery platform may contribute to the development of nanoparticle-based cancer vaccines.

Oncolytic virotherapy has been identified as a promising immunotherapy approach in recent studies. However, some limitations still need to be overcome. Tumor immune evasion and compromised immune surveillance are the main challenges in oncolytic virotherapy [310]. Mechanistic investigations are necessary to reveal how oncolytic viruses interact with the host immune system. A thorough understanding of the action mechanisms of oncolytic viruses will provide new insight into the development of tumor-specific oncolytic virotherapies. The pre-established antiviral immunity induced by infection or treatment can effectively limit the replication of oncolytic viruses, diminishing their efficacy in destroying tumor cells [311]. Injection of high doses of oncolytic viruses may result in exacerbated inflammation, non-specific infection and organ failure [312]. Oncolytic viruses and infected cells can be eradicated by the host immune system, leading to the insufficient viral loads for elimination of cancer cells [313]. The employment of nanotechnology-based approaches can reduce unwanted immune responses against oncolytic viruses, mitigate adverse immune effects and enhance the treatment efficacy. It is expected that nanotechnology advancements are poised to bring oncolytic virotherapy to a new landscape. However, translation of nanotechnology into clinical practice encounters substantial obstacles, such as feasibility of large-scale manufacturing and toxicity concerns [314]. Continual efforts should be invested to explore the safety and effectiveness of nanotechnology-based oncolytic virotherapy.

Nanotechnology for cytokine therapy

Interleukin-2

The IL-2-loaded porous nanoparticle (BALLkine-2) minimized systemic adverse effects of IL-2 and increased the half-life of IL-2 compared to free IL-2 [254]. BALLkine-2 treatment increased infiltration of CTLs into the melanoma and resulted in more significant tumor control than conventional IL-2 treatment. BALLkine-2 produced an effective synergistic therapeutic outcome with anti-PD-1 treatment in an orthotopic melanoma model. In vivo experiments indicated that the anticancer activity of 5-fluorouracil (5-FU) and IL-2-loaded cyclodextrin nanoplexes was superior to free 5-FU in CRC-bearing mice [255]. Linking the PEG polymer chains to the protein structure is able to extend the half-life by increasing its molecular weight, reducing protein clearance by kidneys and non-specific interactions. PEGylation of proteins can increase the solubility and protect them from protease-mediated degradation. PEGylation of IL-2 is a promising strategy for systemic delivery of this cytokine. NKTR-214 is a PEGylated IL-2 that is formed by conjugating six PEG chains to the lysine residues of a mutated IL-2 protein (aldesleukin) [256]. High level of PEGylation conceals the bioactivity of IL-2 and improves its pharmacokinetic profiles [315]. Upon internalization, the PEG chains gradually detach from IL-2 via hydrolysis, unleashing bioactive IL-2. The density and position of PEGylation affect the interaction of IL-2 with its receptors. In NKTR-214, the position of PEG chains on IL-2 are predominantly located in the interface of IL-2/IL-2 receptor α (IL-2Rα) complexation, thus, the PEG chains significantly reduce the affinity of IL-2 to IL-2Rα [257]. NKTR-214 promoted the expansion and activation of NK cells, CD4⁺ T cells, and CD8⁺ T cells while inhibited Treg cell expansion [258]. NKTR-214 administration was tolerated in patients with advanced or metastatic solid tumors. Importantly, NKTR-214 induced tumor regression and durable disease stabilization. Several clinical trials were conducted to investigate the efficacy of the combined therapy of NKTR-214 with ICIs in patients with solid tumors. However, clinical studies showed that NKTR-214 in combination with nivolumab was not superior to nivolumab monotherapy in patients with advanced melanoma and RCC, and the objective response rate (ORR) of the combinatorial therapy didn’t meet the statistically significant expectation [259, 260]. In addition, the combination therapy showed higher toxicity than the monotherapy in treated patients. NKTR-214 treatment-associated toxicities resulted in the termination of these trials on the combinatorial therapies. Another PEGylated IL-2, THOR-707, promoted drug retention in the tumor tissue, activated CD8⁺ T cell-mediated immune responses, and thus retarded tumor growth in melanoma-bearing mice [261]. THOR-707 monotherapy and combination therapy with ICIs showed a tolerable safety profile and beneficial clinical activity in patients with different solid tumors [262, 263]. IL-2-containing proteoliposomal vaccine (referred to as Oncoquest-L) was safe and induced tumor-specific type I cytokine response in patients with follicular lymphoma [264]. It also induce a persistent complete response in one patient. Currently, Oncoquest-L is under phase 2 trial (NCT02194751) as monotherapy in follicular lymphoma patients.

Interleukin-12

IL-12-loaded nanoparticles showed tumor accumulation and low toxicity compared with IL-12 without carriers [265]. Delivery of IL-12 through nanoparticles induced proinflammatory immune responses and led to long-term survival of mice with ovarian cancer. PLGA nanosphere-encapsulated IL-12 demonstrated a rapid agent release and alleviated disease progression in an orthotopic murine model of metastatic osteosarcoma [266]. IL-12 mRNA-loaded polyethylenimine-modified porous silica nanoparticles (PPSNs) induced a high-level production of the target protein within the tumor and contributed to immunogenic cancer cell death [267]. In vivo studies revealed that intratumoral administration of IL-12 mRNA-loaded PPSNs remodeled the TME by elevating the ratio of CD8⁺ T cells to Treg cells. Moreover, IL-12 mRNA-loaded PPSNs reinforced the anticancer effect of anti-PD-1 treatment and further improved the OS of melanoma-bearing mice. Intratumoral injection of IL-12 mRNA-loaded LNPs was more effective in retarding melanoma growth than IL-27 or GM-CSF mRNAs [246]. Dual LNP loaded with IL-12 and IL-27 mRNAs induced infiltration of NK and CD8⁺ T cells into tumors and achieved a synergistic anticancer effect without inducing systemic adverse effects.

IL-12-loaded human serum albumin (HSA) nanoparticles were conjugated onto CAR-T cells to generate IL-12 nanostimulant-engineered CAR-T cell (INS-CAR-T) biohybrids [268]. The release of IL-12 from INS-CAR-T biohybrids increased the secretion of C–C motif chemokine ligand 2 (CCL2), CCL5, and CXCL10, effectively inducing infiltration of CD8⁺ CAR-T cells into lymphoma. INS-CAR-T biohybrids significantly enhanced the antitumor activities of CAR-T cells and achieved efficient therapeutic outcomes in lymphoma-bearing mice. IL-12 mRNA-loaded calcium carbonate nanoparticles prevented glioma development by activating CTLs in tumors and promoting IFN-γ production [269]. A tumor-targeted polymetformin-conjugated nanoplatform was fabricated for the co-delivery of cisplatin and IL-12-encoding plasmid [270]. This nanosystem facilitated drug internalization and accumulation in cancer cells. IL-12-loaded nanoparticles activated immune effector cells (NK cells and CD8⁺ T cells) and thus exhibited efficient antitumor efficacy in lung cancer-bearing mice. Li et al. [271] developed a therapeutic nanoplatform (TNP) that co-delivered IL-12 and DOX to achieve chemo-enhanced immunotherapy for HCC. IL-12 and DOX-loaded TNPs exhibited prolonged circulation in the blood and efficient accumulation in HCC. Upon internalization by cancer cells, IL-12 and DOX were released from TNPs into the TME. The released DOX induced cancer cell death, while IL-12 promoted macrophage polarization into the M1 phenotype, thereby eliciting enhanced immune responses and augmenting the anticancer effect of DOX. As a result, TNPs inhibited HCC growth without significant side effects and improved OS in HCC-bearing mice. EGEN-001 (GEN-1) is a lipopolymer-mediated IL-12 plasmid delivery system to facilitate IL-12 delivery in vivo [272]. Preclinical studies indicated that GEN-1 treatment markedly suppressed tumor growth in vivo and improved animals’ survival [272, 273]. Based on these encouraging results, subsequent clinical trials on GEN-1 were carried out. In a phase 2 clinical trial, GEN-1 monotherapy was not well tolerated in patients with platinum-resistant ovarian cancer, and limited therapeutic activity was observed [274]. In contrast, GEN-1 combined with carboplatin and docetaxel chemotherapy showed good tolerability in platinum-sensitive recurrent ovarian cancer yet the clinical effectiveness remained to be further improved [275]. In a phase 1 clinical trial, GEN-1 combined with PEGylated liposomal DOX presented biological activity and beneficial clinical effects in patients with ovarian cancer [276]. Clinical trials currently underway are intensively focusing on enhancing the potency of this therapeutic approach [316]. GEN-1 in combination with chemotherapies may be an effective therapeutic strategy for the treatment of ovarian cancer. MEDI1191, an LNP formulation encapsulating IL-12 mRNA, was found to significantly inhibit tumor growth by activating systemic immune responses in various murine tumor models [277]. Moreover, MEDI1191 exhibited a synergistic effect when combined with anti-PD-L1 treatment through induction of T cell expansion. Preclinical evidence provides robust support for the feasibility of translating MEDI1191 into clinical practice. The clinical benefits of MEDI1191 in combination with durvalumab was evaluated in a phase 1 clinical trial in patients with advanced solid tumors [252]. Consequently, this combinatorial treatment presented favorable safety profiles and anticancer efficacy. Another LNP formulation encapsulating self-replicating RNA encoding IL-12 (referred to as JCXH-211) in combination with anti-PD-1 antibody triggered antitumor immunity and induced tumor regression in multiple mouse solid tumor models [278]. JCXH-211 is now under phase 1 clincal trial (NCT05539157) for the treatment of solid tumors.

Other cytokines

IL-29-loaded exosomes exhibited a stable release of IL-29, improved the half-life of released agents, and demonstrated superior targeting efficiency [279]. Therefore, IL-29-encapsulated exosomes exerted cytotoxic effects against various cancer cells in vitro. Exosomes can be used as a drug transportation system in cancer immunotherapy in the future due to its high delivery efficiency and low toxicity. IFN-γ-loaded PEGylated liposomes displayed efficient accumulation in colon cancer and promoted the conversion of M2 macrophages into M1 macrophages [280]. Consequently, liposomal formulations containing IFN-γ were effective in treating colon cancer in murine tumor models. TGF-β1-loaded chitosan nanoparticles were able to suppress the malignant characteristics of cervical cancer cells by enhancing the secretion of macrophage inflammatory factors [281].

Chemokines

Synthetic protein nanoparticles (SPNPs) encapsulating the transcytotic peptide iRGD was found to inhibit the CXCL2/CXCR4 pathway in a murine model of glioblastoma [282]. This led to a decrease in the infiltration of CXCR4⁺ monocytic MDSCs (M-MDSCs) into the TME and promoted ICD, which triggered tumor-specific immune reactions and enhanced cancer cell sensitivity to radiotherapy. The combination of iRGD-loaded SPNPs and radiation therapy contributed to long-term survival in glioblastoma-bearing mice by inducing persistent antitumor immune memory responses. Overall, SPNP-based immunotherapy demonstrated significant clinical translational applicability. Nanoparticles encapsulating CXCL10 increased the infiltration of both innate immune cells (NK cells) and adaptive immune cells (IFN-γ⁺ Th1 CD4 cells and effector CD8 cells) into the lungs in a breast cancer spontaneous lung metastasis model [283]. This immunotherapy suppressed the progression of lung metastasis, extended animal survival, and triggered systemic immune reactions that inhibited the expansion of distant tumors following re-challenge.

Although preclinical studies have suggested the therapeutic effect of cytokine therapy, the clinical efficacy is still not satisfactory due the poor pharmacokinetics and severe adverse toxicity [317]. The nanoparticle-based delivery systems can effectively address the issue of low curative effects of cytokine therapy. Targeted delivery of cytokines through nanoparticles protects cytokines from rapid degradation, and allows their targeted and sustained release, thus bypassing unwanted immune suppression and improving the therapeutic efficacy. Nanoparticles remain stable in the bloodstream, minimizing exposure to healthy tissues and lowering the chances of toxicity. As a result, cancer patients could experience a more tolerable and effective dose, leading to improved treatment outcomes. Altogether, compared to recombinant cytokine proteins, nanoformulations have better efficacy and reduced side effects because of their higher bioavailability and targeted delivery. However, it should be noted that nanoparticles introduce the possibility of unpredictable adverse effects in cancer patients. Beyond the well-known hazards linked to poor degradation, DNA damage or metal-induced central nervous system toxicity, nanoformulations may also cause persistent, chronic, and often irreversible immune-related side effects, adding another layer of complexity to their utilization [318]. Therefore, efficiently reducing nanotoxicity while preserving consistent anti-tumor benefits in patients treated with cytokine nanoformulations remains an ongoing significant challenge.

Potential clinical implications of nano-immunotherapy

The combination of nanomedicine and immunotherapy has shown encouraging preclinical therapeutic outcomes. So far, the anticancer efficacy of many nanomedicines, such as Abraxane, Doxil and mRNA nanovaccines, has been tested in clinical trials (Table 3) [319].

Table 3 Clinical trials of nanomedicine-combined immunotherapy in cancer

Full size table

Abraxane

Abraxane is a nanoformulation of paclitaxel encapsulated in albumin nanoparticles as the delivery platform [347]. Atezolizumab, a PD-L1 blocking antibody, is used in the immunotherapy of several advanced or metastatic cancers in the clinical setting [348]. In phase 3 clinical trial in patients with PD-L1 immune cell-positive metastatic TNBC, Abraxane plus atezolizumab improved the median OS (21 months) compared to placebo plus Abraxane (18.7 months) [320]. Treatment with atezolizumab and Abraxane led to an improvement in pathological complete response (pCR)/residual cancer burden class I (RCB-I) rate (46%) in patients with anthracycline (AC)-resistant TNBC compared with historical controls (5%) [321]. The addition of a PD-L1 inhibitor, durvalumab, to Abraxane-based neoadjuvant chemotherapy improved invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and OS in patients with early TNBC [322]. Abraxane treatment improved the ORR after PD-(L)1 blockade therapy, with a durable response of 13% and acceptable adverse events in patients with advanced NSCLC [323]. The disease control rate (DCR) for Abraxane-treated patients was 86.2%. The median progression-free survival (PFS) and OS were 5.6 and 11.9 months, respectively, in NSCLC patients. In a phase I/II trial, 16 out of 46 patients with advanced NSCLC had a partial response after the administration of an anti-PD-1 antibody (pembrolizumab), carboplatin, and Abraxane, corresponding to an ORR of approximately 35% [324]. The median PFS and OS were 5.6 and 15.4 months, respectively. The combination of pembrolizumab, carboplatin, and Abraxane contributed to an overall response rate of 48.0% in patients with metastatic TNBC [325]. The median PFS and OS for the patient cohort were 5.8 and 13.4 months, respectively.

The checkpoint inhibitor targeting PD-1 (camrelizumab), in combination with Abraxane and carboplatin, achieved a complete response rate of 9.8% in patients with advanced esophageal squamous cell carcinoma (ESCC) [326]. The regimen of camrelizumab plus Abraxane and carboplatin resulted in 2-year RFS and OS rates of 67.9% and 78.1% in ESCC patients [327]. Furthermore, patients who had a major pathologic response (MPR) achieved significantly higher 2-year RFS and OS rates. Another study revealed that intensive cycles of camrelizumab plus Abraxane and capecitabine resulted in complete and MPR rates of 33.3% and 64.3% in advanced ESCC patients [328]. The 2-year DFS and OS rates were 92.3% and 97.6%, respectively. Collectively, camrelizumab plus Abraxane and capecitabine facilitated tumor regression and improved survival outcomes in advanced ESCC patients. The safety and efficacy of camrelizumab plus Abraxane and epirubicin were investigated in early TNBC patients [329]. Consequently, 64.1% and 89.7% of patients had complete and partial responses. Moreover, camrelizumab plus Abraxane and epirubicin showed a manageable safety profile in early TNBC patients. In a single-arm, phase 2 trial, the administration of camrelizumab plus cisplatin and Abraxane resulted in an ORR of 98% in patients with locally advanced cervical cancer [330]. No serious toxicities or treatment-related deaths were observed in these patients. Taken together, this combined therapy demonstrated promising anticancer activity and a tolerable safety profile in patients with locally advanced cervical cancer. In a prospective, single-arm, phase 2 study, patients with resectable ESCC were enrolled and treated with a PD-1 inhibitor (tislelizumab) combined with conventional chemotherapy comprising carboplatin and Abraxane [331]. The rates of MPR and pCR for ESCC patients were 57.5% and 40%. Combined treatment of CAR T-EGFR cells, Abraxane and cyclophosphamide was safe in patients with metastatic pancreatic cancer [332]. The combined therapy resulted in a median OS of 4.9 months. Metastatic lesions in the liver were alleviated, and the population of central memory T cells was increased in pancreatic cancer patients who had stable disease following treatment. Ota et al. [333] conducted a phase 1/2 clinical study to test the clinical benefit of DC-based immunotherapy combined with standard chemotherapy employing gemcitabine plus Abraxane in pancreatic cancer patients. No severe adverse cascades were observed in patients receiving the combined treatment. The median PFS and OS were 8.1 months and 15.1 months, respectively, in patients after vaccinations. The clinical activity of the CD40 agonistic monoclonal antibody sotigalimab, gemcitabine, and Abraxane, with or without nivolumab, was assessed in patients with pancreatic adenocarcinoma [334]. This combined treatment achieved an ORR of 58% in treated patients.

Doxil

Doxil, a PEGylated liposomal formulation of DOX, is the first approved nanomedicine product used in cancer treatment [349]. In an open-label, single-arm, phase 2 study, the combined treatment of chemotherapy, comprising gemcitabine, vinorelbine, and Doxil, plus the anti-PD-1 antibody camrelizumab, resulted in an ORR of 74% in patients with relapsed/refractory primary mediastinal B-cell lymphoma (rrPMBCL) [335]. The 2-year PFS and OS rates were 48.2% and 81.5% in patients, with 78% exhibiting tumor regression. Thus, camrelizumab plus Doxil-based chemotherapy showed anticancer activity in rrPMBCL patients. EGEN-001 (GEN-1) is an immunotherapeutic agent that consists of a plasmid expressing human IL-12, formulated with a gene delivery system [350]. When combined with Doxil, GEN-1 led to a clinical benefit rate of 86% in patients with recurrent or persistent epithelial ovarian cancer (EOC) [276]. In a phase 2 study, the Doxil plus IL-12 regimen was well tolerated in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma [336]. Furthermore, this combination therapy resulted in a high response rate (83.3%) in these cancer patients. The clinical benefit of IL-18 in combination with Doxil was examined in patients with platinum-resistant recurrent ovarian cancer [337]. The drug combination yielded a 6% partial response rate and a 38% stable disease rate, resulting in a median PFS of 4.5 months.

mRNA nanovaccines

Currently, many LNP-based mRNA vaccines are under clinical investigation. The neoantigen vaccine GRT-R902 (self-amplifying RNA formulated in LNPs), combined with an individualized, heterologous chimpanzee adenovirus (ChAd68), the anti-PD-1 antibody nivolumab, and the anti-CTLA-4 antibody ipilimumab, was safe and well tolerated in patients with advanced metastatic solid tumors [338]. This combination treatment induced neoantigen-specific CD8⁺ T cell responses and improved OS in patients with microsatellite-stable CRC. The mRNA-4650 vaccine is comprised of an mRNA backbone that encodes defined neoantigens, mutations in driver genes (TP53 and KRAS), and HLA-I-predicted epitopes formulated in LNPs [339]. This vaccine induced neoepitope-specific T cell responses in patients with metastatic gastrointestinal (GI) cancer. No severe side effects were observed in treated patients. The combination of the mRNA-4650 vaccine and other immunotherapies may represent a novel therapeutic approach for treating patients with epithelial cancers. Atezolizumab, uridine mRNA-lipoplex nanoparticles (mRNA neoantigen vaccine), and a combined chemotherapy regimen efficiently increased the population of neoantigen-specific T cells in 50% of pancreatic cancer patients [97]. Patients with expanded T cells (responders) had a longer median RFS than patents without vaccine-expanded T cells (non-responders). mRNA-4157 is a lipid encapsulated vaccines encoding 34 neoantigens and can induce antitumor immune responses [351]. mRNA-4157 was well tolerated and safe in patients with solid tumors [340]. Importantly, mRNA-4157 combined with pembrolizumab achieved remarkable clinical responses in cancer patients, which encouraged the progression of this mRNA nanovaccine to phase 2 clinical trials. In the phase 2 clinical study, mRNA-4157 in combination with pembrolizumab demonstrated an acceptable safety profile and extended RFS in melanoma patients [341]. mRNA-2416, a LNP vaccine incorporating human OX40L-encoding mRNA, was well tolerated and induced immune responses in patients with solid tumors and lymphoma [342]. The mRNA-based LNP encoding OX40L, IL-23 and IL-36γ (mRNA-2752), alone or in combination with durvalumab, was safe and tolerable and exerted a persistent treatment effect in patients with lymphoma or advanced solid tumors [343]. Another clinical study indicated that mRNA-2752 could drive cytokine responses and promote CD8⁺ T cell expansion in patients with melanoma and triple negative breast cancer (TNBC) [344]. The mRNA-LNP vaccine FixVac (BNT111) that targets four melanoma-associated antigens, alone or in combination with anti-PD-1 treatment, led to durable objective responses and disease stabilization in melanoma patients [345]. Particularly, antigen-specific cytotoxic T cell responses with magnitudes comparable to adoptive T-cell therapy were observed in some responders. These encouraging results advance follow-up clinical trials on BNT111 [352]. A LNP mRNA vaccine (BNT112) targeting five prostate-specific tumor-associated antigens (PSAs) had a manageable safety profile and triggered intensive immune and PSA responses in patients with prostate cancer [346]. Two clinical trials (NCT04163094 and NCT05142189) are exploring the FixVac BNT115 that encodes three ovarian-specific antigens in patients with ovarian cancer and metastatic NSCLC [96]. In addition, another personalized neoantigen-specific LNP-mRNA vaccine (BNT122) is presently under clinical investigation (NCT03289962, NCT03815058, NCT04161755, and NCT04486378) in patients with solid tumors.

Despite the great promise of cancer nanovaccines, their successful translation into clinical use still faces significant challenges. Here, we list several key issues: (1) Accurate architecture of cancer nanovaccines stands as a key prerequisite for effective immune cell engagement and stability, ensuring the uniformity and efficacy of nanovaccines. Moreover, scalable production and inter-batch quality control of cancer nanovaccines are critical for their utility in the clinical setting. Thus, standardized and reproducible synthesis procedures and strict quality monitoring technologies must be established. (2) Nanoparticles may interact with diverse biological substances within the human body, thus inducing alterations in the physicochemical properties of nanoparticles. Hence, a comprehensive exploration of the terminal metabolites is also imperative. An ongoing research endeavor is indispensable for the assessment of pharmacodynamic and pharmacokinetic properties of different nanovaccines and development of techniques that monitor antigen release rates. (3) Although many cancer nanovaccines showed therapeutic potential in preclinical studies, but the majority of them failed to offer clinical benefit to cancer patients [353]. A variety of factors influence the effectiveness of cancer nanovaccines, including low delivery efficiency, rapid clearance, tumor heterogeneity, immune tolerance, and absence of suitable tumor antigens [354]. Low delivery efficiency and specificity of nanovaccines can be improved by engineering and optimizing the physicochemical properties of nanomaterials. For instance, hybrid nanoparticles incorporating polymers have been manipulated to facilitate controlled mRNA release, and antibody-conjugated LNPs and selective organ-targeting (SORT) LNPs may promote drug accumulation in the target tissues [355]. Modification of nanoparticle composition and improved encapsulation techniques can increase the stability of nanoparticles and promote drug retention within nanoparticles. For RNA-based nanovaccines, the inherent instability and in vivo translation efficiency of RNAs are fundamental limitations [356]. Optimizing untranslational regions (UTRs) may increase mRNA translation efficiency and facilitate tissue-specific mRNA translation [357]. The advancements in RNA biology and nanotechnology-based delivery systems are set to accelerate the translation of RNA-based nanovaccines towards clinical application. Tailored cancer vaccines based on neoantigens will be an excellent therapeutic option for treating cancers with high intratumoral heterogeneity. Identification of tumor-specific antigens is a fundamental prerequisite for the development of personalized cancer nanovaccines. Nevertheless, it is arduous to obtain precise antigen sequencing through current techniques. The combination of biological sciences with AI-assisted computer simulation algorithms may help to discover more vaccine candidates. Furthermore, the variations in the immune system between preclinical animal models and humans are also responsible for unsatisfactory treatment outcomes in clinical trials. Thus, the development of new animal tumor models in which disease mechanisms are more similar to humans may compensate for the differences. The establishment of patient-derive xenograft models will drive the advancement of personalized cancer vaccines. (4) The interplay between nanoparticles and the host immune system, as well as their vivo distribution, has yet to be fully deciphered. Some nanocarriers (e.g., LNP) are inherently immunogenic, which can act as an immune adjuvant. Meanwhile, they could induce effector immune cell dysfunction and impair antitumor immune responses [358]. Further study is necessary to figure out how to reduce the adverse effects and to tip the balance in favor of efficient antitumor immunity. Given the TME complexity during cancer progression, the combination of cancer nanovaccines and conventional therapies (e.g., ICIs and radiation treatment) presents a promising strategy to potentiate immune responses and improve therapeutic efficacy [359]. In addition, undesired adverse immune effects associated with nanovaccines can be mitigated through targeted interventions within TME or precise immunoregulation. (5) The long-term safety profile of cancer nanovaccines necessitates systemic investigation in the context of their deployment. However, the assessment of nanovaccine-related toxicity is currently in its early stages. Special attention should be paid to the emergence of autoimmune responses.

Conclusions and future perspectives

Nanoformulations have emerged as a highly investigated topic in the field of onco-immunotherapy. Their application in clinical practice would bring about a great revolution in cancer management due to their inherent properties, including biocompatibility, low toxicity, high stability, and precise targeting [129]. However, there are many hurdles encountered when aiming to translate nano-immunotherapies from the bench to the bedside. First, nanoparticles are much complicated compared to small molecule drug formulations. Several physicochemical characteristics, such as size, structure, composition, and surface properties, have an impact on the in vivo performance of nanomedicine formulations [360]. The physicochemical features of nanoparticles appear to significantly differ following administration due to interactions with biological molecules (e.g., protein corona), which makes it difficult to assess their performance in vivo [361]. The distribution, excretion, metabolism, pharmacokinetics, and pharmacodynamics of various nanoparticles must be thoroughly investigated in both preclinical and clinical studies. Secondly, another challenge faced by cancer nanomedicine is the rapid non-specific removal of nanoparticles by the reticuloendothelial system (RES), which is composed of phagocytic immune cells [362]. This significantly reduces the bioavailability of nanoparticles at the tumor site after systemic administration and may lead to off-target toxicity to RES organs, such as the liver and spleen. Modifying nanoparticles or camouflaging phagocyte surfaces can prolong the circulation time of nanoparticles and improve their pharmacokinetic properties [363]. The most effective strategies for inhibiting RES uptake include reduction of nanoparticle size and stabilization of nanoparticles with PEGs. Nevertheless, completely avoiding the RES system has not yet been achieved. Thirdly, difficulty in nanoparticle targeting and penetration in tumors is a fundamental problem that must be overcome. The delivery of nanoparticles to tumors is mediated via both active and passive targeting modes [364]. In the active mechanism, ligand molecules (e.g., antibodies and peptides) on the surface of nanoparticles can specifically bind to tumor antigens, facilitating nanoparticle entry into tumors [365]. For passive tumor targeting, nanoparticles predominantly accumulate at tumor sites through an EPR effect. The extent of nanoparticle accumulation varies depending on multiple factors, including the type of tumor models, the type of targeting ligands, the size of nanoparticles, the surface charge of nanoparticles, the blood circulation lifetimes, angiogenesis, and the degree of tumor vascularization [366]. To address this issue, extensive research interest has been gathered around designing tumor-targeting nanocarriers that release drug payloads in response to specific chemical and biological conditions (e.g., pH or temperature) in the TME [367, 368]. Such nanoparticles may preferentially accumulate at the tumor sites, enhancing the bioavailability and efficacy of encapsulated or conjugated bioactive agents. Particularly, nanoparticle size and surface charge are key features that can be modified to improve the targeting specificity and efficiency of nanoparticles [366]. Fourthly, the concern regarding the toxicity of nanoparticles is an important area of research. Exposure to nanoparticles may lead to harmful nano-bio interactions and other downstream mechanisms that can potentially induce side effects and nanotoxicity. These effects include genotoxicity, immunotoxicity, neurotoxicity, pulmonary toxicity, and vascular dysfunction [369]. Before being used in clinical settings, all developed nanosystems must undergo toxicological studies. Currently, there is a scarcity of comprehensive data on the toxicity of nanoproducts. Interestingly, the available experimental results on nanoparticle toxicological profiles are conflicting and paradoxical, which may be attributed to the intricate interactions between different physicochemical parameters and corresponding biological systems. Additionally, many variables such as exposure route, dose and duration also influence the pathological effects of nanoparticles. Therefore, it is crucial to establish standardized and unified procedures for the systematic evaluation of nanotoxicity under different circumstances in order to obtain accurate toxicological data. In order to fully assess nanoparticle toxicity, the structure and physicochemical features of nanoparticles need to be thoroughly defined and understood. Furthermore, significant attention should be given to elucidating the sophisticated mechanisms of nanotoxicity in biologically and physiologically relevant models. Improved understanding of nanotoxicology may lead to the development of innovative strategies to reduce nanotoxicity, with the ultimate goal of harnessing the full potential of nanotechnology in cancer therapy. Last but not least, there are striking differences between preclinical tumor models and tumors in patients. It should be noted that tumors in patients are more complex and heterogeneous than animal tumor models. Thus, it is of great significance to corroborate the therapeutic efficacy and outcome of nanoformulations in large cohorts of cancer patients. The effect of the TME or other therapeutics on nanoformulation performance in patents is a fundamental research subject that has yet to be fully deciphered and awaits improved understanding.

To conclude, nanocarriers may represent a promising therapeutic regimen for cancer treatment and support the development of more effective treatments. Numerous nanomaterials have been used as efficient vehicles for chemotherapeutic agents or immune modulators, including exosomes, liposomal formulations, and virus-like nanoparticles. These nanosized carriers can be tailored to specifically transfer bioactive cargos to the tumor site. Particular research interest has focused on developing a series of tumor-targeting nanocarriers for cancer therapeutic implications. The utilization of tumor-targeting nanoproducts leads to increased drug accumulation at the tumor site, higher cancer cell penetration, and improved therapeutic effect, culminating in enhanced cytotoxicity against cancer cells while maintaining minimal toxicity toward healthy tissues. Nanoformulations combined with immunotherapy offer collaborative therapeutic efficiency and have great application potential for cancer therapy. Notably, before entering the clinic, substantial research efforts are necessary to verify the biosafety and efficacy of the developed nanocarriers for human use.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ICIs:: Immune checkpoint inhibitors
GLOBOCAN:: Global cancer observatory data
TME:: Tumor microenvironment
EPR:: Enhanced permeability and retention
APC:: Antigen-presenting cell
DC:: Dendritic cell
MHC:: Major histocompatibility complex
DLN:: Draining lymph node
TCR:: T cell receptor
PD-1:: Programmed cell death-1
PD-L1:: Programmed cell death-ligand 1
CTLA-4:: Cytotoxic T lymphocyte-associated antigen-4
BTLA:: B and T lymphocyte attenuator
LAG-3:: Lymphocyte activation gene-3
TIM-3:: T cell immunoglobulin and mucin domain-containing protein-3
TIL:: Tumor-infiltrating lymphocyte
CAR:: Chimeric antigen receptor
CEA:: Carcinoembryonic antigen
CRC:: Colorectal cancer
CLL:: Chronic lymphocytic leukemia
ADC:: Antibody–drug conjugate
ADCC:: Antibody-dependent cell-mediated cytotoxicity
CDC:: Complement-dependent cytotoxicity
SLP:: Synthetic long peptide
IFN-α:: Interferon-α
RCC:: Renal cell carcinoma
PBMC:: Peripheral blood mononuclear cell
mCRPC:: Metastatic castrate-resistant prostate cancer
HPV:: Human papillomavirus
HER2:: Human epidermal growth factor receptor 2
RFS:: Recurrence-free survival
PDAC:: Pancreatic ductal adenocarcinoma
ECHO-7:: Enteric cytopathic human orphan virus type 7
CFDA:: China Food and Drug Administration
T-VEC:: Talimogene laherparepvec
HSV-1:: Herpes simplex virus-1
GM-CSF:: Granulocyte–macrophage colony-stimulating factor
MSC:: Mesenchymal stem cell
IL:: Interleukin
CTL:: Cytotoxic T lymphocyte
Th1:: T helper 1
TGFβR1:: Transforming growth factor-β type I receptor
STING:: Stimulator of interferon genes
IFN-I:: Type I interferon
Treg:: Regulatory T
nm:: Nanometers
DOX:: Doxorubicin
HIV:: Human immunodeficiency virus
NSCLC:: Non-small cell lung cancer
GBM:: Glioblastoma multiforme
nBSA:: Bovine serum albumin nanocapsule
PBA:: Phenylboronic acid
IgG:: Immunoglobulin G
SA:: Sialic acid
Fc:: Fragment crystallizable
PpIx:: Protoporphyrin IX
ROS:: Reactive oxygen species
PDT:: Photodynamic therapy
IDO:: Indoleamine-2,3-dioxygenase
GzB:: Granzyme B
siRNA:: Small interfering RNA
PLGA:: Poly(lactic-co-glycolic-acid)
OVA:: Ovalbumin
BBB:: Blood-brain barrier
CCM:: Cancer cell membrane
ICD:: Immunogenic cell death
Ce6:: Chlorin e6
MDSC:: Myeloid-derived suppressor cell
TNF-α:: Tumor necrosis factor-α
TLR:: Toll-like receptor
CpG:: Cytosine phosphate guanine
ODN:: Oligodeoxynucleotide
pDC:: Plasmacytoid dendritic cell
EGFR:: Epidermal growth factor receptor
LNP:: Lipid nanoparticle
cNP:: Cationic nanoparticle
CCR4:: C-C motif chemokine receptor 4
CXCR4:: C-X-C motif chemokine receptor 4
TNBC:: Triple-negative breast cancer
EGFRvIII:: Epidermal growth factor receptor variant III
IL-15SA:: Interleukin-15 super-agonist
TMZ:: Temozolomide
GITR:: Glucocorticoid-induced tumor necrosis factor receptor
CAT:: Catalase
PDA:: Polydopamine
ICG:: Indocyanine green
FOXP3:: Forkhead box P3
αCSF1R:: Anti-colony-stimulating factor 1 receptor antibody
αCD47:: Anti-CD47 antibody
imNA:: Immunomodulating nanoformulation
MPLA:: Monophosphoryl lipid A
α-CD40:: Anti-CD40
PTEN:: Phosphatase and tensin homologue
PI3K:: Phosphatidylinositol 3-kinase
Akt:: Protein kinase B
TLS:: Tumor lysate
DPPA-1:: D-peptide antagonist
EnS:: Engineered Salmonella
PEG:: Polyethylene glycol
STAT3:: Signal transduction and activator of transcription 3
TADC:: Tumor-associated dendritic cell
PCP:: Poria cocos polysaccharides
rCD44v:: Recombinant CD44v
FAPPEP:: Fibroblast activation protein α-specific epitope peptides
CAF:: Cancer-associated fibroblast
ECM:: Extracellular matrix
HMGN1:: High-mobility group nucleosome-binding protein 1
MPN:: Metal-phenolic network
MDP:: Muramyl dipeptide
OPSCC:: Oropharyngeal squamous cell carcinom
HCC:: Hepatocellular carcinoma
EBV:: Epstein-Barr virus
mOVA:: OVA-encoding mRNA
OS:: Overall survival
AI:: Artificial intelligence
Ad:: Adenoviral vector
SVV:: Seneca Valley virus
SCLC:: Small cell lung cancer
5-FU:: 5-fluorouracil
IL-2Rα:: Interleukin-2 receptor α
ORR:: Objective response rate
HSA:: Human serum albumin
CCL2:: C-C motif chemokine ligand 2
TNP:: Therapeutic nanoplatform
SPNP:: Synthetic protein nanoparticle
M-MDSC:: Monocytic myeloid-derived suppressor cell
pCR:: Pathological complete response
RCB-I:: Residual cancer burden class I
AC:: Anthracycline
iDFS:: Invasive disease-free survival
DDFS:: Distant disease-free survival
PFS:: Progression-free survival
ESCC:: Esophageal squamous cell carcinoma
MPR:: Major pathologic response
rrPMBCL:: Relapsed/refractory primary mediastinal B-cell lymphoma
EOC:: Epithelial ovarian cancer
AIDS:: Acquired immunodeficiency syndrome
GI:: Gastrointestinal
PSA:: Prostate-specific tumor-associated antigen
SORT:: Selective organ-targeting
UTR:: Untranslational region
RES:: Reticuloendothelial system

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Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China
Man Wang, Fei Yu & Yuan Zhang

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Man Wang
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Fei Yu
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Yuan Zhang
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Conceptualization, Supervision, Investigation, Writing - Original draft preparation, M.W.; Investigation, Visualization, F.Y.; Writing - Reviewing and Editing, Y.Z. All authors have read and agreed to the published version of the manuscript.

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Wang, M., Yu, F. & Zhang, Y. Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges. Mol Cancer 24, 26 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-024-02214-5

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Received: 24 September 2024
Accepted: 25 December 2024
Published: 18 January 2025
DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12943-024-02214-5

Present and future of cancer nano-immunotherapy: opportunities, obstacles and challenges

Abstract

Introduction

Types of cancer immunotherapy

Immune checkpoint inhibitors

Adoptive cell therapy

Antibody-based targeted therapy

Cancer vaccines

Oncolytic viruses

Cytokine therapy

Clinically approved nano-based therapeutics for cancer therapy

Lipid-based nanoparticles

Polymeric nanoparticles

Protein-based nanoparticles

Metallic-based nanoparticles

Mechanisms of action of nanodrug delivery systems in improving immunotherapeutic efficacy

Nanotechnology for immune checkpoint blockade therapy

Nanocarrier-mediated alteration of immune checkpoint molecules

Combined treatment of nanotechnology and immune checkpoint inhibitors

Nanotechnology for adoptive cell therapy

Innate immune cell-based immunotherapy

T cell-based immunotherapy

Nanotechnology for antibody-based targeted therapy

Nanotechnology for cancer vaccines

Tumor lysate nanovaccines

Tumor antigen-loaded nanoparticles

Peptide nanovaccines

TLR agonist-conjugated antigen nanoparticles

Viral nanovaccines

mRNA nanovaccines

Nanotechnology for oncolytic virotherapy

Nanotechnology for cytokine therapy

Interleukin-2

Interleukin-12

Other cytokines

Chemokines

Potential clinical implications of nano-immunotherapy

Abraxane

Doxil

mRNA nanovaccines

Conclusions and future perspectives

Data availability

Abbreviations

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding author

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher’s Note

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Keywords

Molecular Cancer

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