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By integrating eight single\u2010cell RNA sequencing datasets and nine multicenter transcriptomic cohorts, the dual impact of AG in PDAC is delineated. AG shifts residual malignant cells from basal toward a more indolent classical phenotype and remodels the TME into a more heterogeneous and intricate landscape. Specifically, AG activates tumor\u2010associated mast cells (TAMCs), reprogrammes myofibroblastic cancer\u2010associated fibroblasts (myCAFs) into inflammatory CAFs (iCAFs), and enhances suppressive crosstalk between TAMCs, iCAFs, and T cells via the macrophage migration inhibitory factor (MIF) axis. Concurrently, AG reduces exhausted T cells and regulatory T cells while enriching cytotoxic natural killer T cells, reshaping the immune milieu in a manner potentially favorable for immunotherapy. In orthotopic and subcutaneous PDAC models, genetic ablation of TAMCs using Kit\n                    <jats:sup>W\u2010sh<\/jats:sup>\n                    mice or pharmacologic stabilization using sodium cromoglycate and the MIF antagonist ISO\u20101 synergistically improves AG efficacy, with further benefit observed upon addition of anti\u2010PD\u20101 therapy. These findings reveal a previously unrecognized mechanism of AG therapy\u2010induced immunosuppression and nominate TAMCs\u2010MIF signaling as a tractable target to optimize neoadjuvant strategies in PDAC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509930","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:29:26Z","timestamp":1761762566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting Mast Cell Activation and MIF\u2010Mediated Remodelling Enhances Chemotherapy Response in Pancreatic Cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3745-9459","authenticated-orcid":false,"given":"Libo","family":"Wang","sequence":"first","affiliation":[{"name":"Pancreas Center Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine Tianjin Key Laboratory of Digestive Cancer Tianjin's Clinical Research Center for Cancer  Tianjin P. 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