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While exhaustion is driven by chronic antigen exposure in the immunosuppressive tumor microenvironment, leading to a reversible state of diminished functionality, senescence reflects a more permanent, age\u2010 or stress\u2010induced arrest in cellular proliferation and effector capacity. Together, these processes represent formidable barriers to sustained anti\u2010tumor immunity. In this review, we dissect the molecular underpinnings of T cell exhaustion and senescence, revealing how these dysfunctions synergistically contribute to immune evasion and resistance across a range of solid tumors. We explore cutting\u2010edge therapeutic approaches aimed at rewiring the exhausted and senescent T cell phenotypes. These include advances in immune checkpoint blockade, the engineering of \u201carmored\u201d CAR\u2010T cells, senolytic therapies that selectively eliminate senescent cells, and novel interventions that reinvigorate the immune system's capacity for tumor eradication. By spotlighting emerging strategies that target both exhaustion and senescence, we provide a forward\u2010looking perspective on the potential to harness immune rejuvenation. This comprehensive review outlines the next frontier in cancer immunotherapy: unlocking durable responses by overcoming the immune system's intrinsic aging and exhaustion, ultimately paving the way for transformative therapeutic breakthroughs.<\/jats:p>","DOI":"10.1111\/acel.70055","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T22:48:01Z","timestamp":1743806881000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Harnessing Immune Rejuvenation: Advances in Overcoming T Cell Senescence and Exhaustion in Cancer Immunotherapy"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6886-177X","authenticated-orcid":false,"given":"Tesfahun Dessale","family":"Admasu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Cedars\u2010Sinai Medical Center  Los Angeles California 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