The multifaceted landscape of T cell exhaustion in organ transplantation: From molecular mechanisms (epigenetics, transcription, metabolism) to induction strategies.

T cell exhaustion is a state of T cell dysfunction resulting from persistent antigenic stimulation, characterized primarily by the high expression of inhibitory receptors, metabolic reprogramming, and epigenetic remodeling. T cell exhaustion is closely associated with immune responses in chronic infections, tumor escape, and organ transplantation. In transplantation immunology, T cell exhaustion plays a dual role: moderate exhaustion can promote immune tolerance and reduce graft rejection, while excessive exhaustion may weaken the defensive capabilities of the immune system, increasing the risk of infection and tumorigenesis. Therefore, effective regulation of T-cell exhaustion has become a crucial issue in the field of immunotherapy. Epigenetic or metabolic interventions may offer novel insights for achieving graft-specific tolerance. Further studies can focus on precise modulation of T-cell exhaustion through metabolic reprogramming, epigenetic regulation, and immune checkpoint inhibition, ultimately enhancing the efficacy of transplantation immunology and immunotherapy. This review focuses on the molecular phenotype, metabolic patterns, and mechanisms of epigenetic changes in exhausted T cells. It also explores the research progress of T cell exhaustion in organ transplantation. Furthermore, the review introduces strategies to induce T cell exhaustion, discussing how these strategies can effectively reduce the side effects of immunosuppressive therapy and promote graft tolerance.