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Here, the functional human endogenous retroviruses\u2010K envelope (HERV\u2010K Env) subunit transmembrane (K\u2010TM) is identified as a potent viral immune checkpoint that induces CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell anergy and elicits immune evasion\u00a0in acute myeloid leukemia (AML) and pancreatic duct adenocarcinoma (PDAC). K\u2010TM subunits are highly expressed in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and\u00a0enriched in sera of cancer patients. K\u2010TM\u2010low CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells show potent tumor\u2010killing ability, whereas K\u2010TM\u2010high CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells are incapable of eliciting anti\u2010tumor effects. Both intracellular and extracellular K\u2010TM inhibit CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation\u00a0and cytokine release, leading to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell anergy. Mechanistically, K\u2010TM directly binds to the ITAM domain of CD3\u03b5 receptor via its transmembrane domain (TMD), inhibiting CD3\u03b5 phosphorylation and disabling TCR signaling. In mouse models, K\u2010TM reduces CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration in tumor tissues and elicits immune evasion. Targeting K\u2010TM reverses CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell anergy, restores T cell\u2010mediated tumor cell killing and regresses PDAC in animal model. The findings for the first time define viral immune checkpoint K\u2010TM subunit as potent driving force of immune evasion and represent a conceptually new target for immune therapies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202417432","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T11:14:28Z","timestamp":1755083668000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HERV\u2010K TM Subunit Elicits CD8\n                    <sup>+<\/sup>\n                    T Cell Anergy and Tumor Immune Evasion via Targeting CD3 Coreceptor \u03b5 in AML and PDAC"],"prefix":"10.1002","volume":"13","author":[{"given":"Mengyuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310009 China"},{"name":"Institute of Hematology Zhejiang University  Hangzhou 310009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310009 China"},{"name":"Institute of Hematology Zhejiang University  Hangzhou 310009 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyuan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Hematology and Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310009 China"},{"name":"Institute of Hematology Zhejiang University  Hangzhou 310009 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