CD8+ T cell exhaustion driven by metabolic reprogramming

CD8⁺ T cells are central to adaptive immunity, with their function tightly linked to cellular metabolism. Naïve T cells rely on oxidative phosphorylation, effector T cells shift to aerobic glycolysis for rapid proliferation, and memory T cells depend on fatty acid oxidation and efficient mitochondrial respiration. In chronic infections and tumors, CD8⁺ T cells often enter an exhausted state, marked by sustained inhibitory checkpoint expression, impaired proliferation and cytotoxicity, and a distinct transcriptional profile driven by factors such as TOX. The tumor microenvironment (TME) imposes metabolic constraints-nutrient competition, lipid accumulation, hypoxia, and metabolite stress-promoting exhaustion. Key metabolic dysregulations include reduced glycolysis, mitochondrial dysfunction, lipid-induced ferroptosis, amino acid scarcity, and hypoxia-mediated HIF-1α signaling. These factors create a self-reinforcing metabolic imbalance that limits T cell plasticity and anti-tumor activity. Emerging strategies aim to restore T cell function by targeting metabolism, including enhancing glycolysis and mitochondrial fitness, modulating lipid and amino acid pathways, and combining metabolic interventions with immune checkpoint blockade or adoptive cell therapy. Understanding the interplay between metabolism and T cell exhaustion provides opportunities to improve durable anti-tumor immunity. This review highlights recent advances in CD8⁺ T cell metabolic regulation, the impact of the TME, and therapeutic approaches to reinvigorate exhausted T cells.