Targeting Immune Cell Metabolism for Cancer Immunotherapy
Metabolic reprogramming is a fundamental regulator of immune cell fate and function in the tumor microenvironment (TME), though the relative contributions of individual metabolic pathways vary across immune cell subsets, tumor types, and disease stages. Competition for nutrients, hypoxia, and the accumulation of immunosuppressive metabolites reshape the TME's metabolic landscape, driving functional exhaustion of antitumor immune cells while promoting the persistence of immunosuppressive populations. These metabolic adaptations have emerged as critical determinants of immune evasion, therapeutic resistance, and responses to cancer immunotherapy. In this review, we examine immune cell metabolism from four complementary perspectives: the physiological metabolic programs of major immune cell populations and their remodeling within the TME; the functional consequences of metabolic reprogramming for antitumor immunity; the principal metabolic drivers, including hypoxia, nutrient competition, and suppressive metabolites; and current therapeutic strategies targeting key immunometabolic pathways, with particular emphasis on glutamine, fatty acid, and lactate metabolism. We further discuss emerging metabolic modulators, their interactions with immune checkpoint blockade, and the opportunities and limitations of combining metabolic intervention with established cancer therapies. Finally, we highlight major translational challenges, including metabolic heterogeneity, limited clinical validation, biomarker identification, and the need for standardized metabolomic and single-cell approaches to enable precision immunometabolism. A more comprehensive understanding of immune cell metabolic regulation may facilitate the development of biomarker-guided therapeutic strategies that selectively restore antitumor immunity while minimizing systemic toxicity, thereby advancing the next generation of personalized cancer immunotherapies.