Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.

T cell exhaustion is an adaptive dysfunctional state driven by chronic antigen exposure and an immunosuppressive tumor microenvironment, which significantly impedes effective antitumor immunity and T cell therapies. This progressive loss of effector function and memory potential is governed by the complex and coordinated interplay of epigenetic, transcriptional, epitranscriptomic, and metabolic networks, which collectively establish stable exhaustion-associated programs. Emerging evidence demonstrates that modulating these layers, whether permanently or transiently, can reverse exhaustion and reinvigorate T cell function. Furthermore, core metabolites serve as shared cofactors, directly linking cellular metabolism to these epigenetic and epitranscriptomic changes. Characterizing these multilayered regulatory mechanisms is critical for developing novel strategies to reprogram exhausted T cells and improve therapeutic efficacy against cancer.