Metabolic–immune nexus in tumor microenvironment: From mechanistic insights to therapeutic opportunities

Abstract The metabolic–immune interplay within the tumor microenvironment (TME) is a critical determinant of tumor progression and immune evasion, presenting significant therapeutic opportunities for enhancing antitumor immunity. The TME is characterized by hypoxia, acidosis, and nutrient depletion, and is also profoundly shaped by the metabolic reprogramming of cancer cells, including enhanced glycolysis, as well as amino acid and lipid metabolism. These metabolic alterations establish an immunosuppressive niche, restricting nutrient availability for effector T cells while enriching the environment with metabolites such as lactate, kynurenine, and adenosine. These metabolites impair the function of cytotoxic T lymphocytes and natural killer cells, while also promoting the survival and activity of regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. Immune cell function within this challenging milieu is dictated by metabolic adaptability: Effector T cells succumb to metabolic exhaustion, whereas regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells exhibit metabolic flexibility that sustains their survival and suppressive functions. Therapeutic strategies that target cancer cell metabolism or enhance the metabolic fitness of immune cells offer promising approaches to mitigating immunosuppression within the TME. Notably, combining metabolic modulators with existing immunotherapies holds great potential for amplifying antitumor responses. Nonetheless, critical hurdles for clinical translation remain, including target specificity, potential toxicities, and adaptive metabolic plasticity. Further investigation into metabolic reprogramming and precision immunotherapy, guided by emerging biomarkers, is critical for optimizing therapeutic efficacy and improving patient outcomes by fully leveraging the metabolic–immune axis.