Fig. 1

Overview of the immunometabolic landscape in cancer across multiscales. a Schematic depicting the typical immunosuppressive TME of solid tumors: immunometabolic hallmarks (left) and heterogenous immune components (right) within the TME. b Nutrient competition between anti-cancer arm (left) and pro-cancer arm (right) in the TME. Core resources, including oxygen, glucoses, amino acids, and lipids, are priorly occupied by pro-cancer immune cells. c Factors from TOE regulate immunometabolism of cancer, including neuronal factors, hormones, physical exercises, diets, pharmaceuticals, and microbiomes. d Immunometabolic interventions rescue exhausted CD8⁺ TILs. Prior to these interventions, CD8⁺ TILs face limitations due to poor nutrition, toxic metabolites build-up, mitochondrial dysfunction, and excessive co-inhibition (left). Treatment with ICBs or 'equipped' with CARs can partially alleviate CD8⁺ TILs exhaustion and rescue their metabolic phenotypes, but they may not completely eliminate solid tumors (middle). The activation of PGC-1α/PPAR through pharmacological or genetic means can enhance the strength of CD8⁺ TILs/CAR-T cells, empowering them to effectively combat solid tumors (right). CAF, cancer-associated fibroblast; CAR, chimeric antigen receptor; DC, dendritic cell; ECM, extracellular matrix; FAO, fatty acid oxidation; ICB, immune checkpoint blocker; IFNγ, Interferon-gamma; MΦ, macrophage; MDSC, myeloid-derived suppressor cell; Mono, monocyte; NK, natural killer cell; OXPHOS, oxidative phosphorylation; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PGC1-α, peroxisome proliferator-activated receptor-γ coactivator-1α; PPAR, peroxisome proliferator-activated receptor; TAM, tumor-associated macrophage; Tconv, conventional T cell; TIL, tumor-infiltrating lymphocytes; TME, tumor microenvironment; TNFα, tumor necrosis factor-alpha; TOE, tumor organismal environment; Treg, regulatory T cell; αPD-1, anti-programmed death 1