Ciliated cells prevent tumorigenesis through an immune-independent mechanism of STING-mediated tumor suppression
Mitigating DNA damage in the fallopian tube epithelium (FTE) is essential for preventing tubo-ovarian high-grade serous carcinoma (HGSC). Here we demonstrate that Stimulator of Interferon Genes (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 TNFa 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. These findings redefine ciliated cells as key guardians of genome integrity rather than passive bystanders and implicate early loss of STING-high ciliated cells as a pivotal event in HGSC initiation with potential relevance for prevention and therapeutic intervention. Overall design: Organoids derived from wild-type mouse (B6) oviductal epithelium were cultured in the presence of PBS (control) or human follicular fluid (treatment) for 24 h (4 replicates per condition for a total of 8 samples).