Metabolic Regulation of T Cell Exhaustion

Cytotoxic CD8 T cells play a crucial role in controlling tumor progression. However, T cells infiltrating tumor tissues upregulate inhibitory receptors, reduce cytokine secretion, and lose their killing function, a state known as exhaustion. Thus, preventing or reversing T cell exhaustion is essential for sustaining a successful antitumor immune response. Recent studies have shown that T cell immunity not only requires the three primary signals—antigen receptor signaling, costimulation, and cytokines—but is largely shaped by endogenous and ambient metabolites as a fourth regulatory signal. Therefore, metabolic changes in the tumor microenvironment, caused by tumor cell proliferation and tissue remodeling, have a significant impact on the function of tumor-infiltrating T cells. This paper will review mechanisms by which three major types of metabolites—carbohydrates, lipids, and amino acids—influence T cell exhaustion in the tumor microenvironment, providing insights and directions for exploring metabolic targets in antitumor immunity.