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

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.