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To gain insights into immune escape mechanisms and discover critical molecules in anti-tumor immunity, we performed an immune checkpoint screening using transcriptome profiling and immunohistochemistry analyses. We identified CD276 as an independent immunosuppressive molecule that correlates with poor EBVaGC prognosis. Our in vitro and in vivo experiments demonstrate the role of CD276 in inducing T cell apoptosis and diminishing chemokine secretion, thereby dampening immune response and facilitating tumor progression. Mechanistically, we discovered that YAP\/TEAD4 chromatin occupancy at CD276 regulatory regions leads to its transcriptional upregulation in EBVaGC, driven by EBNA1-stimulated MST1\/2-LATS1\/2-YAP signaling. Notably, in a humanized xenograft mouse model, EBVaGC with elevated CD276 levels exhibited resistance to anti-PD1 immunotherapy, while targeting CD276 in combination with PD1 blockade significantly reduced tumor size. Collectively, our findings elucidate the EBNA1-YAP-CD276 axis as a novel mechanism of immune escape in EBVaGC, providing insights for enhanced immunotherapeutic strategies.<\/jats:p>","DOI":"10.1038\/s41419-025-08251-2","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T08:53:23Z","timestamp":1766134403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An EBNA1-YAP signaling axis drives immune escape through CD276 in EBV-associated gastric cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Binhao","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yantao","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Abuhaidar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leung Siu","family":"Kee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5275-789X","authenticated-orcid":false,"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-9334","authenticated-orcid":false,"given":"Gong-Hong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2265-1272","authenticated-orcid":false,"given":"Dazhi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"8251_CR1","doi-asserted-by":"publisher","first-page":"2654","DOI":"10.1016\/S0140-6736(16)30354-3","volume":"388","author":"E Van Cutsem","year":"2016","unstructured":"Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. 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