Retinoic Acid Reprograms Mast Cells Toward a Proinflammatory State to Enhance Antitumor Immunity

Mast cells play complex and context‐dependent roles within the tumor microenvironment, yet their molecular characteristics and functional diversity across human cancers remain poorly defined. In this study, single‐cell RNA sequencing and spatial transcriptomics data are integrated to comprehensively map the transcriptional and spatial heterogeneity of mast cells across ten cancer types. A distinct proinflammatory mast cell (PMC) population is identified, characterized by strong antigen‐presenting features and immune‐activating potential. Mechanistic analyses show that retinoic acid (RA) signaling drives the polarization of PMCs through activation of RARα, which promotes CIITA‐mediated MHC‐II expression, CXCL16 secretion, and T cell recruitment and activation. Across multiple cancer types, tumors with higher PMC abundance are associated with more favorable clinical outcomes. These findings reveal the pivotal role of RA–RARα–CIITA signaling in mast cell reprogramming and suggest that pharmacologic induction of proinflammatory mast cells may represent a promising approach to enhance antitumor immunity.