Shared and context-specific mechanisms of T cell exhaustion in chronic viral infections and cancer: Transcriptional, metabolic, epigenetic, and therapeutic perspectives.

T cells are crucial for defending against viral infection and cancer by eliminating infected or transformed cells and establishing immune memory. However, persistent antigenic stimulation in chronic infections or tumors drives T cells into a dysfunctional state known as exhaustion. This state is characterized by reduced proliferation and effector functions, upregulation of inhibitory receptors like PD-1, LAG-3, and CTLA-4, and alterations in transcriptional, epigenetic, and metabolic programs. T cell exhaustion is driven by both intrinsic factors, including changes in transcription factor networks and metabolic dysfunction, and extrinsic factors, such as continuous antigen exposure and an immunosuppressive microenvironment. Key molecules like PD-1, TOX, and TCF-1 are central to this process, though the complex interactions between intrinsic and extrinsic signals in chronic viral infections and cancers remain poorly understood. This review summarized T cell exhaustion in chronic viral infections, such as HIV, HBV, and SARS-CoV-2, as well as in tumors, emphasizing shared mechanisms and context-specific differences. We focused on the roles of transcriptional networks, metabolic changes, immune checkpoints, and exhaustion-related signaling. Additionally, we discussed emerging therapeutic strategies, such as immune checkpoint inhibitors, CAR-T cell therapies, cytokine supplementation, and metabolic interventions, based on recent high-impact studies. By integrating insights from both chronic infection and cancer, this review aims to identify common principles of T cell exhaustion and propose strategies to improve clinical outcomes in chronic viral diseases and cancer immunotherapy.