Metabolic Checkpoints in CD8⁺ T Cells within the Tumor Microenvironment: A Comprehensive Review and Emerging Insights

In recent years, a growing number of evidence suggests that cancer is a metabolic disease. Metabolic reprogramming is a hallmark of the TME, where various nutrients, including glucose, lipids, and amino acids, play key roles in regulating tumor development by acting on both tumor cells and immune cells. T cells are the core mediators of anti-tumor immunity. Especially CD8⁺ T cells are considered the primary immune cells involved in the anti-tumor immune response. Upon stimulation by tumor antigens and other immune cells, CD8⁺ T cells undergo metabolic reprogramming through signaling pathways. Metabolites or metabolic checkpoints induce epigenetic changes in key genes, altering the differentiation and effector function of CD8⁺ T cells. This review first elaborates on the anti-tumor functional characteristics and metabolic profiles of CD8⁺ T cells at different stages of differentiation in the TME. Then we focus on the roles of key metabolites and metabolic checkpoints in shaping CD8⁺ T cell differentiation, functionality, and immune responses, specifically through glucose, lipid, and amino acid metabolism. Finally, we discuss the reasons for heterogeneity in the effects of metabolic checkpoints on CD8⁺ T cells and explore potential clinical applications of metabolic checkpoints in treatment. Understanding the correlation between CD8⁺ T cell metabolism and anti-tumor immunotherapy may facilitate the development of new strategies to enhance the efficacy of CD8⁺ T cell-based cancer treatments.