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Utilizing an in vivo CRISPR-Cas9 metabolic enzyme screen, we identified fucosyltransferase 2 (FUT2) as a potent non-catalytic enhancer of RT response. Mechanistically, FUT2 scaffolds the E3 ubiquitin ligase FBXO2, facilitating K362 site-specific ubiquitination and proteasomal degradation of the transcription factor NR2F2. This degradation suppresses expression of the immunosuppressive factor Lipocalin-2 (LCN2), which drives CD8\u207a T cell exhaustion and impedes NK cell infiltration, fostering a radioresistant TIME. Interestingly, we observed that RT could reduce FUT2 transcript levels via an METTL14-mediated m\u2076A RNA methylation, while NR2F2 was identified to transcriptionally upregulate METTL14, establishing a feedforward inhibitory loop that sustains FUT2 suppression. Clinically, FUT2 expression positively correlates with CD8\u207a T cell infiltration and prolonged survival in RT-treated PDAC patients. Preclinically, combining RT with LCN2-neutralizing antibodies elicited synergistic anti-tumor immunity. These results unveil FUT2 as a regulator of PDAC radiosensitivity via the FUT2-FBXO2-NR2F2-LCN2 axis, offering a promising therapeutic target to overcome RT resistance.<\/jats:p>","DOI":"10.1038\/s41419-025-08378-2","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T05:35:42Z","timestamp":1766468142000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["FUT2 enhances anti-tumor immunity in pancreatic cancer radiotherapy by driving FBXO2-mediated degradation of NR2F2"],"prefix":"10.1038","volume":"17","author":[{"given":"Junguo","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6076-5879","authenticated-orcid":false,"given":"Zhuobin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihuang","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-1085","authenticated-orcid":false,"given":"Hua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7886-2143","authenticated-orcid":false,"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9020-1816","authenticated-orcid":false,"given":"Hui","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3946-5748","authenticated-orcid":false,"given":"Xiongjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9422-7828","authenticated-orcid":false,"given":"Kunhua","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"8378_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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All pancreatic cancer samples from PDAC (primary human pancreatic adenocarcinoma) patients were collected during surgical resection or via biopsy after receiving local radiotherapy at The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, from Jan 2018 with follow-up till Aug 2018, approval No.2023(124). All clinical samples were collected with informed consent under Health Insurance Portability and Accountability Act (HIPAA)-approved protocols in accordance with the provisions of the Declaration of Helsinki of 1975 and the Department of Health and Human Services Belmont Report. The clinical information of the patients is summarized in Supplemental Table\n                      \n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"126"}}