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Understanding the intricate interplay between tumor cells and their microenvironment is essential for deciphering the regulatory mechanisms underlying PSC activation. This study sheds light on the critical role of tumor\u2010derived interleukin\u201035 (IL\u201035) in modulating PSC activation, thereby unveiling a promising therapeutic target for mitigating PDAC progression. This study demonstrates that IL\u201035, secreted by PDAC cells, serves as a key mediator of bidirectional communication between PDAC cells and PSCs, exacerbating fibrosis. Specifically, IL\u201035 upregulates the expression of IGFBP2 and Tsp\u20101 in PDAC cells, which subsequently activates PSCs through the IGF\u20101R\/phosphoinositide 3\u2010kinase\/Akt and transforming growth factor beta signaling pathways, respectively. This sequential activation fosters an environment conducive to tumor cell proliferation and migration, ultimately driving accelerated tumor growth. Collectively, these findings indicate that IL\u201035 is a promising therapeutic target whose blockade not only suppresses PSC activation and stromal fibrosis, but also enhances the efficacy of standard chemotherapies (gemcitabine and gemcitabine\/nab\u2010paclitaxel). This provides a strong rationale for its clinical development as a combinatorial strategy in PDAC treatment.<\/jats:p>","DOI":"10.1002\/advs.202509074","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:49:06Z","timestamp":1763117346000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Derived Interleukin 35 Promotes Fibrosis in the Tumor Microenvironment of Pancreatic Cancer by Activating Pancreatic Stellate Cells"],"prefix":"10.1002","volume":"13","author":[{"given":"Hui","family":"Li","sequence":"first","affiliation":[{"name":"Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, National Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer Tianjin's Clinical Research Center for Cancer  Tianjin 300060 P. R. 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