F7 Drives Gastric Cancer Metastasis Through Anoikis Resistance and Tumor Microenvironment Remodeling

Coagulation factor VII (F7) has been implicated in tumor progression; however, its role in gastric cancer metastasis and immune evasion remains incompletely understood. In this study, we identified F7 as a clinically relevant driver of gastric cancer. F7 was highly expressed in tumor tissues and closely associated with lymph node metastasis, poor prognosis, and reduced CD8⁺ T-cell infiltration. Tumor-derived autocrine F7 interacted with ITGA2 on the cancer cell surface and activated ITGA2-associated FAK-NF-κB signaling and promoted invasion, migration, and anoikis resistance. F7 induced PD-L1 expression in a manner partly dependent on ITGA2-mediated PI3K-AKT signaling and promoted collagen I deposition in liver metastatic lesions, which was associated with reduced CD8⁺ T-cell infiltration. Co-immunoprecipitation showed that the K1.2 and K1.3 regions of F7 mediated its interaction with the N-terminal extracellular region of ITGA2. Further investigations identified HNF4A as an upstream transcription factor of F7, with anoikis-associated stress enhancing HNF4A nuclear accumulation and F7 transcription. Notably, ThonningianinA (THA) was identified as a potential F7-targeting small molecule that suppressed F7-associated malignant phenotypes, reduced tumor growth, and enhanced the antitumor efficacy of anti-PD-1 therapy. These findings support F7 as a potential therapeutic target for metastatic gastric cancer.