Metabolic adaptations of immunosuppressive cells in cancer: mechanisms and therapeutic targets

Abstract The tumor microenvironment harbors diverse immunosuppressive cell populations—including regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages and other tolerogenic subsets—that drive immune evasion and therapeutic resistance. These cells are metabolically reprogrammed to sustain their suppressive function and survive under conditions of hypoxia, nutrient deprivation and oxidative stress. Importantly, their metabolic activity not only supports their own fitness but also creates a hostile environment that antagonizes effector T and natural killer cells by depleting essential nutrients, generating inhibitory metabolites, and altering signaling thresholds. This immunometabolic competition reinforces immune dysfunction and limits the efficacy of checkpoint blockade and adoptive cell therapies. Here we delineate the immunosuppressive cell types within the TME, their key metabolic adaptations and the mechanisms by which they suppress antitumor immunity. Finally, we discuss therapeutic strategies aimed at disrupting these metabolic programs to remodel the TME and enhance the success of current and next-generation immunotherapies. Collectively, understanding the metabolic crosstalk between suppressive and effector immune cells will provide new opportunities to design precision metabolic interventions and improve durable responses to cancer immunotherapy.