Mast cell driven immunometabolism as a therapeutic entry point in ESCC.

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive epithelial malignancies, with most patients deriving only modest benefit from surgery, chemoradiotherapy, or immune checkpoint inhibition. Recent studies suggest that tumor metabolic reprogramming and immune dysfunction evolve together and reinforce one another, yet the causal links between these processes remain only partially understood. Mast cells (MCs) represent a stromal population that has received more attention. Although associated with allergic reactions, tissue repair, and inflammatory responses under normal physiology, MCs in ESCC frequently occupy stromal, vascular and hypoxic zones where metabolic stress is most pronounced. This spatial distribution suggests that MCs actively shape tumor metabolic states through the release of lipid mediators, including prostaglandins, leukotrienes, and platelet activating factor (PAF). These mediators amplify lipid metabolic programs in tumor cells and contribute to an immunosuppressive environment in which dendritic cell priming is attenuated, and cytotoxic T cell (CTL) function is progressively impaired. MC-derived cytokines and proteases further remodel the extracellular matrix and reorganize stromal architecture, collectively facilitating the invasion of malignant cells into adjacent tissue. Single cell and spatial transcriptomic analyses have revealed substantial heterogeneity among tumor-infiltrating MCs, indicating that distinct phenotypic subsets engage divergent metabolic and immune circuits and that only a subset may be functionally tumor permissive. These findings have generated increasing interest in therapeutic strategies targeting MC-linked mediators, inhibiting lipid metabolic enzymes, or integrating metabolic modulation with immune checkpoint therapy. A rigorous mechanistic understanding of how MCs coordinate metabolic and immune remodeling in ESCC may ultimately support biomarker-guided patient stratification and inform novel therapeutic combinations capable of overcoming resistance to current treatment modalities.