Abstract Immune cell function is remarkably plastic, allowing T cells, NK cells, and macrophages to transition from resting or quiescent states to proliferative, cytotoxic, or inflammatory programs. These functional shifts are tightly coupled to metabolic reprogramming, which not only fuels energy and biosynthesis but also shapes epigenetic and transcriptional landscapes that guide immune responses. In this review, we highlight how intrinsic metabolic pathways which include glycolysis, fatty acid oxidation, amino acid metabolism, and TCA cycle intermediates, regulate T and NK cell proliferation, cytotoxicity, memory formation, and epigenetic programs. We also examine macrophages, whose polarization into pro-inflammatory M1 or tissue-reparative M2 states is orchestrated by distinct metabolic programs such as arginine metabolism, oxidative phosphorylation, and fatty acid oxidation, with consequences for local immune regulation. We then explore how tumors exploit these metabolic dependencies to create hostile microenvironments that restrict nutrients, accumulate immunosuppressive metabolites, and dampen immune cell activity. Finally, we discuss emerging metabolic interventions designed to restore immune fitness, enhance the efficacy of immune checkpoint inhibitors, and improve the persistence and cytotoxicity of adoptive T cell therapies, including CAR-T cells, in nutrient-deprived and hypoxic tumor niches. By linking immune cell plasticity to metabolic control, this review provides a framework for understanding how metabolism shapes immunity and identifies strategies to harness these pathways for next-generation cancer immunotherapies.
Fenouille et al. (2026) studied this question.