The role of tumor metabolic reprogramming in acquired anti-PD-1/PD-L1 resistance

Tumor metabolic reprogramming is a pivotal mechanism driving acquired resistance to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Under therapeutic pressure, tumor cells undergo extensive metabolic rewiring, encompassing enhanced glycolysis, altered amino acid metabolism, and reprogrammed lipid utilization. This metabolic plasticity intensifies nutrient competition within the tumor microenvironment (TME), leading to the accumulation of immunosuppressive metabolites such as lactate and kynurenine. These metabolites collectively impair effector T cell activation, proliferation, and cytotoxicity, while simultaneously facilitating the expansion and suppressive activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). In parallel, T cells often exhibit metabolic exhaustion, characterized by mitochondrial dysfunction, reduced oxidative phosphorylation, and impaired metabolic flexibility, which ultimately limits their persistence and anti-tumor efficacy despite checkpoint blockade. Moreover, the intrinsic heterogeneity and adaptability of tumor metabolism promote the selection of resistant subclones during immunotherapy, further undermining treatment durability. To overcome these barriers, emerging combinatorial strategies are focusing on integrating metabolic inhibitors, such as lactate dehydrogenase A (LDHA) and IDO1 inhibitors, with immune checkpoint blockade, or on metabolically engineering T cells to enhance their fitness. Future efforts should emphasize precise patient stratification, development of highly selective metabolic modulators, and rational design of combination therapies to improve both the efficacy and long-term durability of cancer immunotherapy.