Immune Exhaustion in Chronic Infection and Cancer: Signaling Pathways and Therapeutic Interventions

Immune exhaustion is a state of sustained lymphocyte dysfunction that occurs following chronic antigenic stimulation and constitutes a shared hallmark of chronic infection and cancer. Beyond being a passive consequence of persistent antigen exposure, it actively drives tumor progression by fostering immunosuppressive microenvironments. Pathogens that evade immune detection to establish chronic infection can directly induce immune exhaustion through sustained inflammatory signaling, thereby crippling cytotoxic T cell-mediated tumor surveillance. This impairment facilitates both de novo tumorigenesis and the aggressive evolution of pre-existing malignancies. This comprehensive review delineates the mechanisms and characteristics of immune exhaustion within the contexts of chronic infection and cancer, as well as its impact on disease progression. Furthermore, we propose a chronic infection-exhaustion-tumor axis and analyze this pathway with reference to specific pathogens. Finally, we provide a critical appraisal of current strategies designed to reverse immune exhaustion and discuss their therapeutic potential and limitations within three defined contexts: chronic infection, cancer, and the interplay between chronic infection and tumor development. By integrating insights from virology and immuno-oncology, this work proposes therapeutic strategies to disrupt the infection-exhaustion-tumor axis, offering a roadmap for precision oncology.