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Here, we review the heterogeneity of <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cells, whereas the identification of <jats:styled-content style=\"fixed-case\">TCF1<\/jats:styled-content><jats:sup>+<\/jats:sup> stem\u2010like <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cells has highlighted their importance in anti\u2010tumor immunity. During tumor progression, <jats:styled-content style=\"fixed-case\">TCF1<\/jats:styled-content><jats:sup>+<\/jats:sup> stem\u2010like <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cells differentiate into cytotoxic Tim\u20103<jats:sup>+<\/jats:sup> terminally differentiated <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cells through mechanisms that remain largely unknown. We recently identified <jats:styled-content style=\"fixed-case\">CD69<\/jats:styled-content> as an important regulator of chronic <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cell responses and showed that blocking <jats:styled-content style=\"fixed-case\">CD69<\/jats:styled-content> function, either through the administration of anti\u2010<jats:styled-content style=\"fixed-case\">CD69<\/jats:styled-content> antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim\u20103<jats:sup>+<\/jats:sup> terminally differentiated <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cells in both tumor\u2010draining lymph nodes (<jats:styled-content style=\"fixed-case\">TDLNs<\/jats:styled-content>) and the tumor microenvironment (<jats:styled-content style=\"fixed-case\">TME<\/jats:styled-content>), thereby enhancing the anti\u2010tumor immune response. These findings suggest that <jats:styled-content style=\"fixed-case\">CD69<\/jats:styled-content> is an attractive therapeutic target that controls the chronic anti\u2010tumor <jats:styled-content style=\"fixed-case\">CD8<\/jats:styled-content><jats:sup>+<\/jats:sup> T cell response.<\/jats:p>","DOI":"10.1111\/cas.70055","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:55:49Z","timestamp":1743137749000},"page":"1500-1507","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differentiation of Cytotoxic CD8<sup>+<\/sup> T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?"],"prefix":"10.1111","volume":"116","author":[{"given":"Ryo","family":"Koyama\u2010Nasu","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology Graduate School of Medicine, Chiba University  Chiba 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