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This review comprehensively delineates the multifaceted heterogeneity of exhausted T (T\n                    <jats:sub>EX<\/jats:sub>\n                    ) cells, tracing their developmental trajectory from precursor exhausted T (T\n                    <jats:sub>PEX<\/jats:sub>\n                    ) cells to terminally differentiated exhausted T (T\n                    <jats:sub>EX<\/jats:sub>\n                    <jats:sub>\u2010term<\/jats:sub>\n                    ) cells. We highlight both distinct and shared exhaustion features across diverse cancer types and spatial niches within the tumor microenvironment. Furthermore, we examine the multi\u2010layer biomarkers that drive and define this state, including characteristic surface inhibitory receptors, core transcription factors, and metabolism\u2010associated molecules. Grounded in this mechanistic understanding, we discuss emerging therapeutic strategies aimed at reversing T cell exhaustion. These range from the optimized application of ICIs and rational combination therapies involving epigenetic or metabolic interventions, to next\u2010generation engineered cell therapies such as chimeric antigen receptor T cell (CAR\u2010T), T cell receptor\u2010engineered T cell (TCR\u2010T), and tumor\u2010infiltrating lymphocytes (TILs), alongside emerging modalities including oncolytic viruses and bispecific antibodies. Finally, we discuss prevailing challenges and future directions, emphasizing that deciphering the heterogeneous landscape of T\n                    <jats:sub>EX<\/jats:sub>\n                    cells, identifying precise biomarkers, and developing temporally controlled combination regimens are imperative to effectively reverse T cell exhaustion and broaden the therapeutic efficacy of cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520634","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:29:17Z","timestamp":1768292957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities"],"prefix":"10.1002","volume":"13","author":[{"given":"Yang","family":"Yu","sequence":"first","affiliation":[{"name":"Faculty of Chinese Medicine and State Key Laboratory of 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