MRGPRX2-Mediated Mast Cell Activation Promotes Malignant Progression of Cutaneous Squamous Cell Carcinoma through IL-17A Release

Cutaneous squamous cell carcinoma (cSCC) is a common keratinocyte-derived malignancy with increasing activated mast cells (MCs) around. Although MCs are abundant in the skin and demonstrate microenvironment-dependent plasticity, their precise role in cSCC pathogenesis remains unclear, particularly regarding activation mechanisms and functional contributions to cSCC progression. In this study, bioinformatics and histopathological analysis revealed that significantly enriched activated MCs in cSCC lesions correlate with adverse prognosis. Mechanistically, tumor cell–MC crosstalk triggered extracellular signal–regulated kinase/protein kinase B hyperactivation, inducing MC degranulation and IL-17A secretion that promoted cSCC cells proliferation, migration, and apoptosis resistance. Notably, these tumor-promoting effects were abrogated by treatment with MC membrane stabilizer sodium cromolyn, MRGPRX2 knockdown, or IL-17A blockade. In vivo studies confirmed that MRGPRX2 deficiency reduced MC activation and decreased IL-17A production, while partially suppressing tumor proliferation and delaying the epithelial–mesenchymal transition process. Collectively, our findings demonstrate that MRGPRX2 serves as a key receptor driving MC activation and IL-17A release in cSCC, thereby driving cSCC progression by establishing a tumor-promoting feedback loop. This discovery provides critical insights into elucidating the role of MCs in cSCC progression and the underlying molecular mechanisms.