Epithelial tumor cells utilize mast cell-derived histamine to regulate perineural invasion

Cancer dissemination by perineural invasion (PNI) is associated with poor outcomes in epithelial malignancies, yet the cellular interactions critical to this process are not fully defined. Single-cell transcriptomic analysis of cutaneous squamous cell carcinoma (cSCC) with PNI highlighted KITLG - KIT signaling activation between keratinocytes and mast cells. Additionally, we observed increased expression of HRH1 on tumor cells, which encodes the H1 histamine receptor. We confirmed these changes in other cancers, including PNI-positive hepatobiliary and oral mucosal tumors. Histamine enhanced tumor invasion into nerve in organoids that recapitulate key features of PNI, an effect rescued by H1-antihistamines. Mechanistically, broad upregulation of matrix metalloproteinases (MMPs) through P38 activation underscored histamine-mediated PNI by enabling collagen degradation in the nerve sheath. Examination of multiple cancer types with PNI showed co-expression of HRH1 and MMP2 on tumor cells as well as type IV collagen loss in involved nerves. Retrospective analysis of >15,000 patient health records in two independent databases demonstrated that H1-antihistamine use improved overall survival and immunotherapy response in cancers that spread by PNI. Together, these data reveal a critical role for mast cells in PNI and present a new therapeutic strategy for targeting this process in epithelial cancers.