Metabolic Regulation of T Cell Exhaustion

Abstract

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.

Keywords

T cell exhaustion / Immunometabolism / Cancer immunology

Acknowledgments

We thank Katrin Sinning for the contribution in figure preparation. Figures were created in BioRender (Agreement number: BR281PFB8J, UR27LABOMN, IY27XB9E7Y, HF281MHUL0).

Author Contributions

Writing—Original Draft Preparation, H.W., M.V.; Writing—Review & Editing, H.W., M.C.P., M.V.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB-TR 338 (“LETSimmun”)—project number: 452881907, SFB 1526 (“PANTAU”), project number: 454193335; SFB 1525 (“Cardio-Immune Interfaces”)—project number: 453989101; SFB 1583 (“DECIDE”)—project number: 49262049; and individual project grants VA882/2-1 and VA882/3-2 to M.V.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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