Loss of Gαq reshapes fibroblast traits and drives tumor-stroma remodeling in oral cancer progression

Abstract Head and neck squamous cell carcinoma is an aggressive malignancy with limited therapeutic options and poor outcomes. A key driver of tumor progression is the tumor microenvironment, particularly cancer-associated fibroblasts, which remodel the extracellular matrix and secrete pro-tumorigenic signals. Emerging evidence suggests that vesicle trafficking pathways regulate these secretory functions, though their role in HNSCC remains unclear. Building on our discovery of Gαq as an autophagy regulator, we investigated how its absence reshapes fibroblast behavior and modulates crosstalk with HNSCC cells. We demonstrate that loss of Gαq reprograms murine fibroblasts into a CAF-like phenotype through deregulated intracellular trafficking and increased ceramide accumulation. Gαq-deficient fibroblasts show increased collagen I deposition, ECM remodeling, and secretion. Their exosomes, enriched in tumor-promoting growth factor receptors, suppress Caveolin-1 in tumor cells and induce an EMT-like phenotype that fuels HNSCC growth. In co-culture and in vivo, Gαq-silenced fibroblasts form “railroad-track” structures guiding cancer cell migration and invasion. Reduced Gαq expression in human fibroblasts recapitulates these features, identifying Gαq as a key regulator of fibroblast plasticity and tumor–stroma interactions in HNSCC progression.