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In gastric cancer (GC), we identify TAGLN2 as a key exosomal mediator. It is co\u2010overexpressed in GC cells and tumor\u2010associated endothelial cells (TECs), and its high endothelial expression correlates with lymph node metastasis and poor prognosis. Functionally, GC\u2010derived exosomes deliver TAGLN2 to endothelial cells (ECs), orchestrating angiogenesis, EndoMT, and the disruption of endothelial junctions. In vivo, exosomal TAGLN2 accelerated tumor growth and lung metastasis by generating abnormal, leaky vasculature and hypoxia. Mechanistically, exosomal TAGLN2 initiates a novel signaling axis: it transcriptionally upregulates\n                    <jats:italic>NRP1<\/jats:italic>\n                    via c\u2010Jun\/SP1 and concurrently induces SEMA4D expression. TAGLN2 then interacts with both NRP1 and SEMA4D to nucleate a stable cytoplasmic ternary complex. This complex dually activates YAP by competitively disrupting NRP1\u2010YAP binding to release YAP from cytoplasmic retention, and simultaneously suppressing Hippo\u2010mediated degradation, operating independently of the canonical SEMA4D\u2010PlexinB1\u2010RhoA\/ROCK pathway. Therapeutically, targeting the TAGLN2 axis synergized with both cisplatin and bevacizumab, potently suppressing tumor progression by impairing neovascularization and promoting vascular normalization. Clinically, exosomal TAGLN2 levels were significantly elevated in GC patient serum. Our study delineates a complete exosome\u2010to\u2010vasculature signaling axis and positions TAGLN2\/NRP1\/SEMA4D\/YAP module as an integrated diagnostic and therapeutic target against metastatic GC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521962","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:54:54Z","timestamp":1773428094000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tumor\u2010Derived Exosomal TAGLN2 Promotes Metastasis by Inducing Vascular Permeability and Angiogenesis via the NRP1\/SEMA4D\/YAP Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuqi","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery Zhongshan Hospital of Xiamen University School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathology Zhongshan Hospital of Xiamen University School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery and Sports Medicine Zhongshan Hospital of Xiamen University School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoquan","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Zhongshan Hospital of Xiamen University School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Xiamen Municipal Key Laboratory of Gastrointestinal Oncology  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihao","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Zhongshan Hospital of Xiamen University School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Xiamen Municipal Key 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