Mitochondrial metabolism and PD-1 blockade: mechanisms and therapeutic opportunities in cancer immunotherapy.

The development of immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has brought about a breakthrough in cancer treatment; nevertheless, therapeutic resistance remains a significant challenge. Recent research shows that mitochondrial metabolism plays an essential role in T-cell function and therapeutic efficacy. Activation of PD-1 inhibits glycolytic metabolism, mitochondrial biogenesis, and oxidative phosphorylation (OXPHOS), resulting in T-cell exhaustion and impaired function. Concurrently, metabolic reprogramming in tumor cells, characterized by increased glycolysis, glutaminolysis, and fatty acid oxidation (FAO), creates an immunosuppressive tumor microenvironment (TME) through nutrient deprivation and the accumulation of metabolites such as lactate and 2-hydroxyglutarate (2-HG). In this review, we analyze the bidirectional relationship between PD-1 signaling and mitochondrial dysfunction and discuss emerging therapeutic approaches that combine metabolic reprogramming with immune checkpoint blockade.