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However, the evolution of this immunosuppressive TME and the underlying mechanisms remain incompletely understood. Here, we construct a dynamic single\u2010cell atlas spanning uninvolved adjacent pancreatic tissue (UNIN), intraductal papillary mucinous neoplasm (IPMN), and PDAC. We confirm the stepwise establishment of an immunosuppressive milieu, accompanied by the emergence of LRRC15\n                    <jats:sup>+<\/jats:sup>\n                    fibroblasts as determinants. Functional assays further identify tumor\u2010derived LAMB3 as a regulator of LRRC15\n                    <jats:sup>+<\/jats:sup>\n                    fibroblast differentiation. Mechanistically, LAMB3 promotes FOSL2\u2010dependent transcriptional activation of LRRC15 through the ITGB1\/FAK\/MAPK signaling axis, ultimately suppressing T cell cytotoxicity. Orthotopic models reveal that LAMB3 overexpression increases the LRRC15 positive area and impairs T cell cytotoxicity, whereas FAK inhibition partially reverses these effects. In parallel, LAMB3 knockdown reduces the LRRC15 positive area and improves the efficacy of PD\u20101 blockade. Moreover, glycolytic reprogramming in PDAC ductal cells upregulates LAMB3 expression and correlates with increased LRRC15\n                    <jats:sup>+<\/jats:sup>\n                    fibroblast enrichment. Clinically, co\u2010enrichment of LAMB3\n                    <jats:sup>+<\/jats:sup>\n                    PDAC ductal cells and LRRC15\n                    <jats:sup>+<\/jats:sup>\n                    fibroblasts is associated with inferior overall survival. Collectively, our findings define a dynamic ductal\u2010fibroblast\u2010immune multicellular axis underlying PDAC pathogenesis and provide insights into potential therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520029","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:31:09Z","timestamp":1779201069000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tumor\u2010Derived LAMB3 Drives Immunosuppressive LRRC15\n                    <sup>+<\/sup>\n                    Fibroblast Formation During Pancreatic Ductal Adenocarcinoma Development"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9061-5442","authenticated-orcid":false,"given":"Xuqing","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Pathology State Key Laboratory of Common Mechanism Research for Major Diseases Peking Union Medical 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