Abstract

CD8⁺ T cell anergy is a critical driver of cancer immune evasion, but the underlying causes and mechanisms remain elusive. Here, the functional human endogenous retroviruses-K envelope (HERV-K Env) subunit transmembrane (K-TM) is identified as a potent viral immune checkpoint that induces CD8⁺ T cell anergy and elicits immune evasion?in acute myeloid leukemia (AML) and pancreatic duct adenocarcinoma (PDAC). K-TM subunits are highly expressed in CD8⁺ T cells and?enriched in sera of cancer patients. K-TM-low CD8⁺ T cells show potent tumor-killing ability, whereas K-TM-high CD8⁺ T cells are incapable of eliciting anti-tumor effects. Both intracellular and extracellular K-TM inhibit CD8⁺ T cell activation?and cytokine release, leading to CD8⁺ T cell anergy. Mechanistically, K-TM directly binds to the ITAM domain of CD3ε receptor via its transmembrane domain (TMD), inhibiting CD3ε phosphorylation and disabling TCR signaling. In mouse models, K-TM reduces CD8⁺ T cell infiltration in tumor tissues and elicits immune evasion. Targeting K-TM reverses CD8⁺ T cell anergy, restores T cell-mediated tumor cell killing and regresses PDAC in animal model. The findings for the first time define viral immune checkpoint K-TM subunit as potent driving force of immune evasion and represent a conceptually new target for immune therapies.