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Inflammatory cancer\u2010associated fibroblasts (iCAFs), a crucial subset of CAFs within the PDAC microenvironment, play a pivotal role in shaping an immunosuppressive microenvironment. In this study, single\u2010cell RNA sequencing analysis is performed to screen for cancer cells\u2010secreted proteins associated with iCAF induction, and PPY (pancreatic polypeptide) is validated as a potent inducer. Unlike previously reported iCAF inducers, PPY is a gastrointestinal hormone predominantly expressed in the pancreas, suggesting that targeting it may have minimal systemic effects. Multiplex immunohistochemistry (mIHC) on human PDAC tissue microarrays, orthotopic allograft mouse models, and co\u2010culture experiments are utilized to validate the crucial role of PPY in iCAF induction. Mechanistic studies integrating mRNA sequencing, immunoprecipitation\u2010mass spectrometry, and molecular docking reveal that PPY induces iCAFs by activating the non\u2010canonical NF\u2010\u03baB pathway through EGFR. Importantly, targeting PPY enhanced the efficacy of anti\u2010PD\u20101 immunotherapy in KPC (\n                    <jats:italic>Kras<\/jats:italic>\n                    <jats:sup>LSL\u2010G12D\/+<\/jats:sup>\n                    ;\n                    <jats:italic>Trp53<\/jats:italic>\n                    <jats:sup>LSL\u2010R172H\/+<\/jats:sup>\n                    ;\n                    <jats:italic>Pdx1<\/jats:italic>\n                    \u2010Cre) mice, as evidenced by reduced tumor burden on PET\u2010CT imaging and improved survival. This research is expected to provide a novel strategy for improving immunotherapy in PDAC by targeting a key inducer of iCAFs.\n                  <\/jats:p>","DOI":"10.1002\/advs.202413432","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T09:30:41Z","timestamp":1743499841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["PPY\u2010Induced iCAFs Cultivate an Immunosuppressive Microenvironment in Pancreatic Cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6773-3952","authenticated-orcid":false,"given":"Mengdie","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"},{"name":"Hubei Key Laboratory of Hepato\u2010Pancreato\u2010Biliary Diseases Tongji Hospital Tongji Medical College 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Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Pittsburgh School of Medicine  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"},{"name":"Hubei Key Laboratory of Hepato\u2010Pancreato\u2010Biliary Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"},{"name":"School of Life Sciences The Chinese University of Hong Kong  Shatin, New Territories Hong Kong 999077 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