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). Here, CD8A is linked to acute myeloid leukemia.