Table 2 pyroptosis-targeted anti-tumor strategies

DHA

NLRP3, caspase-1, GSDMD

BC

Activates caspase-1, induces GSDMD cleavage, promotes IL-1β secretion, facilitates HMGB1 cytoplasmic translocation.

Enhances anti-tumor immune cell activity, promotes anti-tumor factors, reduces immunosuppressive cells, strengthens anti-tumor immune response.

[160]

siRNA- lncRNA-XIST

NLRP3, caspase-1, SOD2

NSCLC

Induces pyroptosis through ROS level upregulation and NLRP3 inflammasome activation

Influences tumor microenvironment through ROS and inflammatory response regulation

[162]

cisplatin

NLRP3, caspase-1, GSDMD

TNBC

Activates NLRP3/caspase-1/GSDMD pathway through long non-coding RNA MEG3 upregulation

Enhances immune response in TME, improves chemotherapy sensitivity

[195]

Anthocyanin

NLRP3, caspase-1, GSDMD, IL-1β

OSCC

Activates NLRP3/caspase-1 pathway, induces GSDMD cleavage,

Enhances anti-tumor immune response, improves chemotherapy sensitivity

[275]

FL118

NLRP3, caspase-1, IL-1β

CC

Activates NLRP3 inflammasome, promotes caspase-1 activation, increases GSDMD expression

Inhibits colorectal cancer cell proliferation, migration, and metastasis, enhances tumor cell sensitivity, promotes local inflammatory response

[276]

siRNA- ATP5F1D

NLRP3, caspase-1

EC

Reduces mitochondrial ROS levels, suppresses NLRP3 inflammasome activation

Affects TME inflammatory response

[277]

XCT790

NLRP3, caspase-1, GSDMD

En-C

Promotes pyroptosis through ERRα downregulation

Enhances cisplatin sensitivity, improves immune response

[278]

Dasatinib

NLRP3, caspase-1, GSDMD

PC, LC

Restores GSDMD activity by countering β5-integrin-mediated suppression through Src-STAT3 pathway

Improves chemotherapy response, enhances immune response

[279]

Doxorubicin

DFNA5, caspase-3

Melanoma

Activates caspase-3 to cleave DFNA5, induces GSDM-mediated pyroptosis

Enhances anti-tumor immune response, increases chemotherapy sensitivity

[280]

4-HBA

caspase-1

LC

Induces transcription of caspase-1 encoding genes

Promotes immune cell recruitment, enhances tumor immune response

[281]

α-NETA

caspase-4, GSDMD

OC

Induces pyroptosis through activation of GSDMD/caspase-4 pathway

Functions both as a direct cytotoxic agent, enhances anti-tumor immunity

[181]

Iron

Tom20, ROS, GSDME

Melanoma

Enhances ROS signaling, leads to Tom20 oxidation and aggregation, promotes Bax transport to mitochondria, releases cytochrome c, activates caspase-3, induces GSDME cleavage

Enhances anti-tumor immune response, promotes tumor cell death

[282]

neobractatin

Tom20, ROS, GSDME

Es-C

Induces GSDME cleavage through ROS/TOM20/BAX signaling pathway

Enhances immune response through pyroptosis induction, inhibits tumor growth

[283]

L61H10

NF-κB, caspase-3, GSDME

LC

Induces pyroptosis through NF-κB pathway inhibition, triggers G2/M phase arrest, promotes transition from apoptosis to pyroptosis

Enhances anti-tumor immune response through transition from apoptosis to pyroptosis

[102]

N-substituted EF24 analog 13d

NF-κB, caspase-3, GSDME

LC

Induces transition from apoptosis to pyroptosis through NF-κB activity inhibition

Enhances anti-tumor immune response through transition from apoptosis to pyroptosis

[103]

BI2536

caspase-3, GSDME

ESCC

Induces caspase-3 activation and GSDME cleavage

Enhances immunotherapy sensitivity

[158]

Tanshinone II A

miR-145, caspase-3, caspase-9, GSDMD

CC

Induces pyroptosis through GSDMD upregulation and caspase-3/9 activation

Enhances anti-tumor immune response

[161]

cisplatin

caspase-3, GSDME

LC

Induces caspase-3 activation, cleaves GSDME, leading to pyroptosis and secondary necrosis

Enhances immunotherapy efficacy through pyroptosis induction and immune response activation

[170]

Paclitaxel

caspase-3, GSDME

LC

Activates caspase-3, leads to GSDME cleavage, induces both pyroptosis and apoptosis

Enhances anti-tumor immune response

[170]

Chalcone Derivative 8

caspase-3

LC

Induces ROS level upregulation

Enhances anti-tumor immune response

[173]

GLE

ROS, caspase-3

BC

Elevates ROS level, activates caspase-3 / GSDME

Prevents capillary tube formation, inhibits tumor adhesion, migration

[174]

5-FU

caspase-3, GSDME

GC

Induces pyroptosis through caspase-3-mediated GSDME cleavage

Improves immunotherapy efficacy through altered cell death mechanisms, affects chemotherapy tolerance

[224]

Pladienolide B

Caspase-3, GSDME

OC

Inhibits SF3B1, reduces BCL2L2, induces caspase-3/GSDME-mediated pyroptosis, releases mtDNA

Activates macrophages via cGAS-STING, increases CTL infiltration, synergizes with immunotherapy, upregulates PD-L1

[244]

Cisplatin

Capase-3/GSDME

SCLC

IR700DX-6T

Mitochondria (TSPO) caspase-3

CRC

Generates ROS, activates p38/MAPK/caspase-3 signaling cascade

Promotes DCs maturation and CD8⁺T cell infiltration, sensitizes to immunotherapy

[284]

CAP

ROS, caspase-9, caspase-3, GSDME

LC, GC

Activates caspase-9 and caspase-3 through ROS generation, leads to GSDME cleavage and pyroptosis

Enhances anti-tumor immune response

[285]

PL analogue L50377

ROS, caspase-3, GSDME

NSCLC

Inhibits NF-κB through ROS generation, leading to pyroptosis

Enhances anti-tumor immune response

[286]

Decitabine + CAP

ROS, caspase-3, GSDME

OC

Upregulates GSDME through DFNA5 gene demethylation, activates caspase-3, inducing pyroptosis

Enhances anti-tumor immune response

[287]

CDT

ROS, caspase-9, caspase-3, GSDME

CRC

Induces GSDME cleavage through ROS/caspase-9/caspase-3 pathway

Enhances anti-tumor immune response

[288]

galanin

caspase-3, GSDME

GBM

Induces both apoptosis and pyroptosis through GSDME and caspase-3 pathway activation

Enhances anti-tumor immune response through dual cell death pathway activation

[289]

Tetraarsenic Hexoxide

caspase-3, GSDME

TNBC

Induces pyroptosis through mitochondrial ROS generation and STAT3 phosphorylation inhibition

Enhances anti-tumor immune response

[290]

Decitabine + Paclitaxel

GSDME

BC (MCF-7/Taxol resistant)

Reverse GSDME enhancer methylation, increases GSDME expression, enables Paclitaxel-induced caspase-3 activation

Restores chemosensitivity to Paclitaxel

[182]

Decitabine

GSDME

OSCC

Reverse GSDME enhancer methylation, increases GSDME expression, enables cisplatin-induced caspase-3 activation

Restores chemosensitivity to cisplatin

[183]

Euphohelioscopin A

GSDME

NSCLC

Activates PKC in NK cells, produces IFN-γ, upregulates GSDME expression

Enhances NK cell-mediated tumor lysis, promotes NK-dependent tumor regression in vivo

[185]

LPS

GSDMD

CRC

Induces pyroptosis through GSDMD expression and GSDMD-N membrane translocation

Enhances tumor cell sensitivity to immune cells, improves chemotherapy efficacy

[186]

Osthole

GSDME

OC

Triggers GSDME-dependent pyroptosis through GSDME expression induction

Enhances anti-tumor immune response

[188]

Disulfiram

GSDMD

CRC

Prevents GSDMD pore formation through covalent modification at Cys191

Enhances immune cell recognition and killing of tumor cells

[199]

Apcin

GSDME

PCa

Inhibits CDC20-mediated GSDME ubiquitination, increases GSDME levels, shifts to pyroptosis

Promotes CD8⁺T cell infiltration, synergizes with anti-PD-L1 therapy, enhances anti-tumor immunity

[243]

Decitabine

GSDME

CRC

Inhibits DNMT1, reverses KIAA1199-mediated GSDME methylation, increases GSDME expression

Reverses immunotherapy resistance associated with high KIAA1199, enhances CD8⁺T cells infiltration, synergizes with ICIs

[184]

Curcumin

ROS, GSDME

HCC

Induces pyroptosis through ROS upregulation and GSDME activation

Promotes anti-cancer effects through apoptosis and pyroptosis regulation

[291]

cadmium

GSDME

TNBC

Induces pyroptosis through ROS generation and NLRP3 inflammasome activation

Enhances anti-tumor immune response, affects immune cell activity

[292]

ORFV

GSDME

PC, melanoma

Induces pyroptosis through caspase-3 activation and GSDME cleavage

Promotes CD8⁺T cell infiltration, enhances anti-tumor immune response

[273]

GOx-Mn/HA NPs

GSDMD

BC

Induces tumor cell pyroptosis through tumor glucose metabolism regulation, combined with anti-PD-L1

Increases PD-L1 expression, activates T cells, enhances anti-PD-L1 immunotherapy efficacy

[217]

GSDMB^NT mRNA@LNPs

GSDMB

BC

Delivers GSDMB^NT mRNA into tumor cells

Enhances response to anti-PD-1 therapy, increases proinflammatory cytokines, promotes DCs maturation, enhances T cell infiltration

[230]

NP-NH-D5

NLRP3

BC, PC

Accumulates lysosomes, assembles in situ nanofiber, triggers LMP, releases CatB, activates NLRP3

Enhances DCs maturation and T cells infiltration, reduces Tregs, inhibits metastasis

[227]

FeMn@R@H

NLRP3

BC

Activates NLRP3 inflammasome through Fe²⁺ and Mn²⁺ release in acidic microenvironment

Induces immunogenic cell death, promotes anti-tumor immune response, enhances DC maturation

[293]

Pd2Sn@GOx-SP

NLRP3

CRC

Induces pyroptosis and disulfidptosis through catalytic ROS generation

Promotes anti-tumor immune response through immunogenic cellular content release, enhances T cell infiltration

[294]

TBD-3 C

ROS, caspase-1, GSDMD

PC

Induces pyroptosis through photodynamic therapy-activated GSDMD cleavage

Promotes M1 macrophage polarization, dendritic cell maturation, and CD8⁺T cell activation

[267]

YBS-BMS NPs-RKC

ROS, caspase-1, GSDMD

PC

Induces immunogenic pyroptosis through NIR-activated ROS generation

Promotes CD8⁺ T cell infiltration and enhances anti-tumor immune response

[226]

C₄H₄Na₂O₄ NPs

ROS, caspase-1, GSDMD

BC

Ionic overload triggers oxidative stress and activates caspase-1

Upregulates MHC-I expression, avoids tumor evasion, enhances antigen presentation

[207]

PSCT NPs

Caspase-1, GSDMD, α-KG, GSDMC

BC

Activates caspase-1/GSDMD and caspase-8/GSDMC-mediated pyroptosis through sodium ion and citrate release

Induces immunogenic cell death, enhances anti-tumor immune response

[213]

HSA@Tz-Ru1

ROS, caspase-1, GSDMD

BC

Activates pyroptosis via ROS generation, activates caspase-1

Two types of ROS lead to significant membrane disruption, enhances anti-tumor immune response

[219]

P.CNF/5-FU

Caspase-1

BC

Activates inflammasome complex and caspase-1, generates ROS, modulates p53 pathway

Enhances anti-tumor immune response, supports hASCs, promotes tissue regeneration

[225]

Cu-Pic/HA NPs

caspase-1, GSDMD

BC

Depletes polyamines, accumulates ROS

Enhances pyroptosis and cuproptosis

[232]

K₃ZrF₇:Yb/Er

ROS, caspase-1, GSDMD

BC

Releases K⁺and [ZrF7]³⁻ ions, accumulates ROS, activates caspase-1

Enhances DCs maturation, increases T cells, inhibits tumor growth and metastasis

[234]

Na₃ZrF₇:x%Yb³⁺

Caspase-1, GSDMD

BC

Ion overload from nanoparticles induces ROS generation, mitochondrial damage

Enhances antitumor immunity, promotes T cell infiltration, and reduces tumor growth

[235]

NaHCO3 NPs

ROS, caspase-1, GSDMD

BC

Induces pyroptosis through lactate metabolism regulation and increases intracellular osmotic pressure

Reverses tumor microenvironment acidity, enhances anti-tumor immune response

[295]

Au–Cu2-xSe@ZIF-8

Caspase-1, GSDMD

Melanoma

Regulates zinc ion levels, induces DNA damage

Enhances anti-tumor immune response

[296]

NIR-II Z1 NPs

ROS, caspase-1, GSDMD

BC

Produces type-I ROS upon irradiation, causes mitochondrial dysfunction

Combined pyroptosis and apoptosis augments immunotherapy, overcomes apoptosis resistance

[284]

MS-275 + V-9302

Caspase-1, GSDMD

UVM

Inhibits mTOR pathway, reduces glutamine uptake, accumulates ROS

Recruits immune cells, enhances immune memory

[297]

As₂O₃-NPs

Caspase-3, GSDME

HCC

Induces G2/M phase arrest and apoptosis, activates caspase-3

Enhances anti-tumor immune response

[187]

Photocatalytic carbon dots

ROS, caspase-3, GSDME

Melanoma, BC

Generates hydroxyl radicals, decreases pH values under radiation, accumulates ROS

Activates antigen-presenting cells, inhibits cancer stem cells, forms long-memory T cells for further tumor prevention

[208]

COF-919

ROS, caspase-3

BC

Generates ROS, leads to lipid peroxidation, activates GPX4-mediated ferroptosis and caspase-3-mediated pyroptosis

Triggers ferroptosis and pyroptosis simultaneously, improves the response rate of immunotherapy

[214]

HCNP

ROS, caspase-3, GSDME

LC

Accumulates ROS under laser irradiation, activates caspase-3, cleavage of GSDME

Enhances effectiveness of immunotherapy, stimulates antitumor immunity

[218]

TiO₂ − _xF_x

ROS, caspase-3, GSDME

CC

Increases oxygen vacancies, improves sono-catalytic efficiency, accumulates ROS

Increases DC maturation, enhances T cell infiltration, reduces M2-polarized macrophages, inhibits tumor recurrence, enhances penetration depth

[220]

Nano-CD

GSDME, caspase-3

Melanoma

Co-delivers CRISPRa plasmid (sgRNA for GSDME) and cisplatin. CRISPRa upregulates GSDME; Cisplatin activates Caspase-3

Enhances DCs maturation and T cells responses, inhibits recurrence and metastasis, synergizes with immunotherapy

[228]

PL@SD

GSDME, caspase-3

BC

DEC upregulates GSDME, SN38 activates caspase-3 and causes DNA damage, activates cGAS-STING

Induces apoptosis-to-pyroptosis switch, enhances DCs maturation, improves innate and adaptive immunity

[229]

Cu-THBQ/AX

ROS, caspase-3, GSDME

BC

Generates ROS, triggers caspase-3, induces the oligomerization of dihydrolipoamide S-acetyltransferase

Pyroptosis, cuproptosis and necrosis results in inflammatory TME, enhances antigen presentation

[231]

Bi₂Sn₂O₇

Caspase-3, NLRP3, GSDMD, caspase-1, p-MLKL, RIPK3

HCC

Generates ROS, induces PANoptosis

Triggers PANoptosis, overcomes therapeutic resistance

[233]

CaZCH NPs

ROS, caspase-3, GSDME

CRC

Induces pyroptosis through Ca²⁺, H₂O₂, and CUR release in acidic environment, leads to mitochondrial Ca²⁺ overload and oxidative stress

Enhances anti-tumor immune response and tumor-associated macrophage reprogram

[298]

M-Cu-T

ROS, caspase-3, GSDME

LC

Induces pyroptosis through photo-activated ROS generation, depletes GSH, activates caspase-3/GSDME pathway

Induces immunogenic cell death, releases DAMPs, enhances anti-tumor immune response

[299]

PHDT-Pt-In

Caspase-3, GSDME

PC

Enhances platinum drug-induced pyroptosis through COX-2 expression inhibition

Increases secretion of immune-promoting factors, promotes CD8 + T cell infiltration

[300]

MCPP

ROS, caspase-3, GSDME

CRC

Releases PTX and ROS, activates caspase-3/ GSDME pathway

Promotes DCs maturation and T cells proliferation, forms memory T cells, enhances ICB therapy

[301]

MPNPs

ROS, caspase-3, GSDME

TNBC

Inhibits STAT3, reduces tumor stemness, generates ROS

Stimulates T cells infiltration, reduces immunosuppressive cells

[302]

MF@SOR

Caspase-1/3, GSDMD, GSDME

HCC

Fe³⁺ activates caspase-1, SOR activates caspase-3

Promotes DCs matration, activates cGAS-STING pathway, reduces tumor recurrence and metastasis

[303]

MMSN-cRGD@Ce6

ROS, Caspase-1/3, GSDMD, GSDME

BC

Generates ROS, mitigates hypoxia, activates caspase-1/3

Promotes immune responses, reduces tumor growth, enhances antitumor efficacy

[304]

GM@LR

Caspase-3, GSDME

TNBC

MnCO generates Mn²⁺ and CO, activates caspase-3 to cleave GSDME

Enhances antitumor immune response, promotes DCs maturation, activates CD8 + T cells.

[305]

nano-Erda@PLT

Caspase-3, GSDME

BLC

Erda activated by ADP, triggers caspase-3, cleaves GSDME

Enhances targeted drug delivery, stimulates immune response

[306]

OPDEA-PDCA

Caspase-3, GSDMD

OS

Inhibits PDHK1, accumulates ROS, releases cytochrome C

Enhances antitumor immune response, reshapes TME

[307]

TPL@TFBF

Caspase-3, GSDME

Melanoma

Inhibits Nrf2, reduces glutathione synthesis, elevates ROS

Enhances DCs maturation, combines with ICB to enhances anti-tumor efficacy, inhibits metastasis

[308]

CG/RH-NPs

Caspase-3, GSDME

BC

Ca²⁺ overload activates ROS generation, CQ blocks autophagy

Enhances CD8⁺ T cell infiltration, promotes tumor immune response, suppresses metastasis

[309]

Apt-OMVs

LPS, caspase-4, GSDMD

BC

Delivers LPS into the tumor cells, triggers caspase-4/5 and caspase-11

Triggers LPS noncanonical pathway, enhances antitumor immunity, reshape TME

[310]