Ciliated cells drive critical STING-mediated tumor suppression in fallopian tube epithelium

Mitigating DNA damage in the fallopian tube epithelium (FTE) is essential for preventing tubo-ovarian high-grade serous carcinoma (HGSC). Here we demonstrate that STING is abundantly expressed in the ciliated cells of the FTE and functions as a critical immune-independent tumor suppressor. Using patient samples, mouse models, and organoid systems, we demonstrate that ciliated cells mount a dual protective response to ovulation-associated genotoxic stress: intrinsic STING-driven apoptosis and extrinsic clearance of neighboring damaged secretory cells via TNFalpha secretion. This surveillance mechanism markedly limits DNA damage accumulation within the epithelial microenvironment. Crucially, while these mechanisms are vital for maintaining homeostasis and reducing genomic instability, they fail to impact p53-deficient precursor lesions as both intrinsic and extrinsic pro-apoptotic processes rely on functional p53 signaling. This study uncovers a previously unrecognized, immune-independent role for STING-high ciliated fallopian tube cells as active guardians of genomic integrity, whose loss creates a permissive niche for HGSC initiation. CONFLICT OF INTEREST STATEMENT: R.D. serves on the scientific advisory board of VOC Health and Repare Therapeutics. DGH is a previous founder and Chief Medical Officer of Imagia Canexia Health. The other authors declare that they have no competing interests.