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CRACD, an actin polymerization regulator, is frequently inactivated in gastric cancer (GC), with enrichment in mucinous subtypes. We found that genetic engineering of murine gastric organoids with\n                    <jats:italic>Cracd<\/jats:italic>\n                    ablation combined with\n                    <jats:italic>Kras<\/jats:italic>\n                    mutation and\n                    <jats:italic>Trp53<\/jats:italic>\n                    loss induced mucinous cell plasticity, disrupted epithelial integrity, and promoted immune evasion. Mechanistically, CRACD loss triggered actin dysregulation, which activated the NF-kB\/COX2 signaling and NADPH oxidase-dependent ROS generation. The resulting oxidative stress stabilized HIF1\u03b1 and transactivated\n                    <jats:italic>PD-L1<\/jats:italic>\n                    , thereby disrupting anti-tumor immunity. Pharmacologic inhibition of HIF1\u03b1 or PD-L1 restored immune surveillance and suppressed tumorigenesis. Clinically, analysis of patient-derived organoids and tissue microarrays demonstrated the inverse correlation between CRACD and PD-L1 expression. These findings identify CRACD inactivation as a crucial event in mucinous plasticity and immune escape in GC, further proposing that the HIF1\u03b1-PD-L1 axis is a therapeutic vulnerability in CRACD-inactivated GC.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-77348-9","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:24:06Z","timestamp":1788283446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRACD loss drives hypoxia-induced immune escape in gastric cancer"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7243-5386","authenticated-orcid":false,"given":"Yoojeong","family":"Seo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinho","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-5972","authenticated-orcid":false,"given":"Kyung-Pil","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-8674","authenticated-orcid":false,"given":"Gengyi","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9092-4652","authenticated-orcid":false,"given":"Shengzhe","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohee","family":"Jun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonhong","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishwa","family":"Venkatesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana","family":"Dhakshinamoorthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2292-5584","authenticated-orcid":false,"given":"Hyunki","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0737-2654","authenticated-orcid":false,"given":"Jae-Il","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"77348_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-024-19104-6","volume":"24","author":"J-L Lin","year":"2024","unstructured":"Lin, J.-L. et al. 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