Oral Fungal Infection Impacts Epithelial Innate Immunity to Promote Local and Distal Squamous Cell Carcinoma Progression.

Abstract

Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. Here, we showed that aggressive human head and neck squamous cell carcinomas (HNSCCs) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL-1β and IL-17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides-induced IL-1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL-1β, and IL-17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL-1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL-1β/IL-1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression.