2. Academic Validation
  3. HERV-K TM Subunit Elicits CD8+ T Cell Anergy and Tumor Immune Evasion via Targeting CD3 Coreceptor ε in AML and PDAC

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

  • Adv Sci (Weinh). 2025 Aug 13:e17432. doi: 10.1002/advs.202417432.
Mengyuan Li 1 2,  Shuwen Zheng 1 2,  Qinyuan Gong 1 2,  Zhaoxing Wu 1 2,  Wen Lei 1,  Wanyue Cao 3 4 5,  Ping Wang 1,  Xuzhao Zhang 1,  Wenbin Qian 1 2,  Yun Liang 1,  Ying Lu 6,  Fenglin Li 6,  Qi Zhang 3 4 5,  Rongzhen Xu 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Institute of Hematology, Zhejiang University, Hangzhou, 310009, China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5 MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 6 Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, 315000, China.
PMID: 40801282 DOI: 10.1002/advs.202417432
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.

Keywords

AML; CD3ε; CD8+ T cell anergy; HERV‐K; PDAC; VICs; immune evasion.

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