Targeting Mast Cell Activation and MIF‐Mediated Remodelling Enhances Chemotherapy Response in Pancreatic Cancer

Neoadjuvant gemcitabine plus nab‐paclitaxel (AG) reprograms pancreatic ductal adenocarcinoma by shifting malignant cells toward a classical phenotype and remodeling the tumor microenvironment. Despite enhancing cytotoxic NKT cells, AG activates tumor‐associated mast cells (TAMCs) and inflammatory CAFs through MIF signaling. Targeting TAMCs or MIF potentiates AG efficacy and synergizes with anti‐PD‐1 therapy, highlighting a promising combination treatment strategy. Abstract Neoadjuvant gemcitabine plus nab‐paclitaxel (AG) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC), yet its effects on the tumor microenvironment (TME) remain incompletely defined. By integrating eight single‐cell 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‐associated mast cells (TAMCs), reprogrammes myofibroblastic cancer‐associated 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 KitW‐sh mice or pharmacologic stabilization using sodium cromoglycate and the MIF antagonist ISO‐1 synergistically improves AG efficacy, with further benefit observed upon addition of anti‐PD‐1 therapy. These findings reveal a previously unrecognized mechanism of AG therapy‐induced immunosuppression and nominate TAMCs‐MIF signaling as a tractable target to optimize neoadjuvant strategies in PDAC. Neoadjuvant gemcitabine plus nab-paclitaxel (AG) reprograms pancreatic ductal adenocarcinoma by shifting malignant cells toward a classical phenotype and remodeling the tumor microenvironment. Despite enhancing cytotoxic NKT cells, AG activates tumor-associated mast cells (TAMCs) and inflammatory CAFs through MIF signaling. Targeting TAMCs or MIF potentiates AG efficacy and synergizes with anti-PD-1 therapy, highlighting a promising combination treatment strategy. Abstract Neoadjuvant gemcitabine plus nab-paclitaxel (AG) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC), yet its effects on the tumor microenvironment (TME) remain incompletely defined. By integrating eight single-cell 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-associated mast cells (TAMCs), reprogrammes myofibroblastic cancer-associated 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 W-sh mice or pharmacologic stabilization using sodium cromoglycate and the MIF antagonist ISO-1 synergistically improves AG efficacy, with further benefit observed upon addition of anti-PD-1 therapy. These findings reveal a previously unrecognized mechanism of AG therapy-induced immunosuppression and nominate TAMCs-MIF signaling as a tractable target to optimize neoadjuvant strategies in PDAC. Advanced Science, Volume 12, Issue 48, December 29, 2025.