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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\u2010mediated tumor surveillance. This impairment facilitates both de novo tumorigenesis and the aggressive evolution of pre\u2010existing 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\u2013exhaustion\u2013tumor 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\u2010oncology, this work proposes therapeutic strategies to disrupt the infection\u2013exhaustion\u2013tumor axis, offering a roadmap for precision oncology.<\/jats:p>","DOI":"10.1002\/mco2.70635","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:12:44Z","timestamp":1772968364000},"source":"Crossref","is-referenced-by-count":6,"title":["Immune Exhaustion in Chronic Infection and Cancer: Signaling Pathways and Therapeutic Interventions"],"prefix":"10.1002","volume":"7","author":[{"given":"Yali","family":"Song","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Shenzhen University General Hospital  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhi","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuemei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanying","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, West China Hospital Sichuan University, Sichuan Clinical Research Center For Laboratory Medicine, Clinical Laboratory Medicine Research Center of West China Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Gastroenterology and Urology Department II, Hunan Cancer Hospital\/the Affiliated Cancer Hospital of Xiangya School of Medicine Central South University; 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