Tumor Cells Hijack Coagulation Signaling to Enable Immune Escape and Metastatic Dissemination
Abstract Lymph node metastasis (LNM) represents a pivotal event in cancer progression and a major determinant of response to immune checkpoint blockade (ICB). Elucidation of the molecular mechanisms linking metastatic dissemination to immune suppression could identify potential therapeutic targets to improve ICB efficacy. Here, we identified the coagulation initiator tissue factor (F3) as a central regulator bridging tumor metastasis and immune evasion in gastric cancer (GC). F3 was significantly upregulated in LNM-positive tumors and correlated with impaired ICB responsiveness and poor clinical outcome. Mechanistically, the intracellular domain of F3 directly bound eEF1A1 to promote STAT3 phosphorylation and induce CCL20 expression, which selectively recruited CCR6+ regulatory T cells (Tregs) to establish an immunosuppressive microenvironment. Disruption of this F3–eEF1A1–STAT3–CCL20 axis with the clinically approved compound olsalazine disodium served as a compelling preclinical proof-of-concept to potently suppress tumor growth, abrogate Treg infiltration, and restore ICB sensitivity, all without perturbing basal coagulation. These findings redefine F3 from a canonical coagulation initiator to a tumor-intrinsic immunomodulator and reveal a druggable vulnerability that uncouples its oncogenic signaling from hemostasis.
Authors
- Muyan Cai (ORCID: https://orcid.org/0000-0002-4646-4391)
- Jiliang Lin
- Zhoukai Zhao
- Baishen Zhang (ORCID: https://orcid.org/0000-0002-9222-4882)
- Zhiwei Zhou (ORCID: https://orcid.org/0000-0003-1338-1220)
- Feiyang Zhang (ORCID: https://orcid.org/0000-0002-3746-9756)
- Xueyi Zheng (ORCID: https://orcid.org/0000-0003-1386-7052)
- Jin‐Ling Duan (ORCID: https://orcid.org/0000-0002-8297-3003)
- Yongqiang Zheng (ORCID: https://orcid.org/0000-0003-3246-2800)
- Sachiyo Nomura (ORCID: https://orcid.org/0000-0003-4293-6205)
- Shuqiang Yuan (ORCID: https://orcid.org/0000-0003-3661-5069)
- Run‐Cong Nie (ORCID: https://orcid.org/0000-0003-3595-6304)
- Shuang Wang (ORCID: https://orcid.org/0000-0002-5558-4029)
- Tao Zhang (ORCID: https://orcid.org/0000-0001-9331-8832)
- Baiwei Zhao (ORCID: https://orcid.org/0009-0004-2125-8657)
- Jierong Chen (ORCID: https://orcid.org/0009-0001-5904-7140)
- Yuanfang Li (ORCID: https://orcid.org/0000-0003-1762-2634)
- Chengcai Liang (ORCID: https://orcid.org/0000-0001-7625-4574)
- Yingbo Chen (ORCID: https://orcid.org/0000-0003-2509-3381)
- Xiao‐Jiang Chen
- Xiaoxia Cai (ORCID: https://orcid.org/0000-0001-8215-852X)
- NianDong Yi (ORCID: https://orcid.org/0009-0001-6110-4079)
- Chunhua Qu (ORCID: https://orcid.org/0009-0008-8688-7269)
- Zi-Qi Zheng (ORCID: https://orcid.org/0000-0002-9607-3882)
- Xin-ke Zhang (ORCID: https://orcid.org/0009-0006-2092-1167)
- Guo-Ming Chen (ORCID: https://orcid.org/0000-0002-4259-1289)
Institutions
- Sun Yat-sen University (CN)
- Hoshi University (JP)
- Sun Yat-sen Memorial Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Oncology in South China (CN)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-11-09
- DOI
- https://doi.org/10.1158/0008-5472.can-25-5733
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00