HERV‐K TM Subunit Elicits CD8 ⁺ T Cell Anergy and Tumor Immune Evasion via Targeting CD3 Coreceptor ε in AML and PDAC

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.