Low-Protein Diet Enhances Anti-Tumor Immunity and Immunotherapy through Microbiota-Derived Uridine Diphosphate-Galactose in Pancreatic Cancer

Low-Protein Diet Enhances Anti-Tumor Immunity and Immunotherapy through Microbiota-Derived Uridine Diphosphate-Galactose in Pancreatic Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Low-Protein Diet Enhances Anti-Tumor Immunity and Immunotherapy through Microbiota-Derived Uridine Diphosphate-Galactose in Pancreatic Cancer Ling Dong, Yueying Chen, Fulin Nian, Shengdi Wu, Wenfeng Liu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5804694/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract This study explored the potential of a low-protein diet (LPD) to modulate the gut microbiota, focusing on pancreatic ductal adenocarcinoma (PDAC) progression and response to immunotherapy. A 25% reduction in dietary protein intake attenuated PDAC development, drove immune activation in the tumor microenvironment (TME) and boosted the immunostimulatory tumor-associated macrophages (TAMs) phenotype. We found the depletion of gut microbiota compromised the anti-tumor effect of LPD. Specifically, a significant increase in the abundance of Blautia coccoides was observed following LPD intervention. Further studies revealed that Blautia coccoides administration inhibited PDAC tumorigenesis and via its metabolite, uridine diphosphate (UDP)-galactose. Mechanistically, UDP-galactose activates the P2Y14R receptor, promoting STAT1 expression and phosphorylation, inducing an immunostimulatory macrophage phenotype. Combining LPD with α-PD1 significantly attenuated tumor burden and improved survival beyond α-PD1 alone. Finally, reduced fecal B. coccoides and serum UDP-galactose were observed in patients with advanced pancreatic cancer. In summary, LPD reshapes the gut microbiota and metabolites to induce anti-tumor immunity via the UDP-galactose/P2Y14R/STAT1 axis, enhancing survival rates in PDAC. Health sciences/Gastroenterology/Gastrointestinal diseases/Pancreatic disease/Pancreatic cancer Health sciences/Oncology/Cancer/Gastrointestinal cancer/Pancreatic cancer Low-protein diet Pancreatic ductal adenocarcinoma Blautia coccoides Uridine diphosphate-galactose Tumor-associated macrophages Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5804694","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":407870326,"identity":"540e18c6-714a-4d62-8eaa-18e7d3b4ce27","order_by":0,"name":"Ling 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diphosphate-galactose, Tumor-associated macrophages","lastPublishedDoi":"10.21203/rs.3.rs-5804694/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5804694/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"This study explored the potential of a low-protein diet (LPD) to modulate the gut microbiota, focusing on pancreatic ductal adenocarcinoma (PDAC) progression and response to immunotherapy. A 25% reduction in dietary protein intake attenuated PDAC development, drove immune activation in the tumor microenvironment (TME) and boosted the immunostimulatory tumor-associated macrophages (TAMs) phenotype. We found the depletion of gut microbiota compromised the anti-tumor effect of LPD. Specifically, a significant increase in the abundance of Blautia coccoides was observed following LPD intervention. Further studies revealed that Blautia coccoides administration inhibited PDAC tumorigenesis and via its metabolite, uridine diphosphate (UDP)-galactose. Mechanistically, UDP-galactose activates the P2Y14R receptor, promoting STAT1 expression and phosphorylation, inducing an immunostimulatory macrophage phenotype. Combining LPD with α-PD1 significantly attenuated tumor burden and improved survival beyond α-PD1 alone. Finally, reduced fecal B. coccoides and serum UDP-galactose were observed in patients with advanced pancreatic cancer. In summary, LPD reshapes the gut microbiota and metabolites to induce anti-tumor immunity via the UDP-galactose/P2Y14R/STAT1 axis, enhancing survival rates in PDAC.","manuscriptTitle":"Low-Protein Diet Enhances Anti-Tumor Immunity and Immunotherapy through Microbiota-Derived Uridine Diphosphate-Galactose in Pancreatic Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-29 04:51:07","doi":"10.21203/rs.3.rs-5804694/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cancer","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcancer","sideBox":"Learn more about [Nature Cancer](http://www.nature.com/natcancer/)","snPcode":"","submissionUrl":"","title":"Nature Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"81be7f97-e3d7-4b03-926c-dc44212b7e6b","owner":[],"postedDate":"January 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":43486121,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases/Pancreatic disease/Pancreatic cancer"},{"id":43486122,"name":"Health sciences/Oncology/Cancer/Gastrointestinal cancer/Pancreatic cancer"}],"tags":[],"updatedAt":"2026-05-09T12:15:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-29 04:51:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5804694","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5804694","identity":"rs-5804694","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}