Ciliated Cells Drive Critical STING-Mediated Tumor Suppression in the Fallopian Tube Epithelium

Mitigating DNA damage in the fallopian tube epithelium (FTE) is essential for preventing tubo-ovarian high-grade serous carcinoma (HGSC). In this study, we demonstrated that the stimulator of interferon genes (STING) is abundantly expressed in the ciliated cells of the FTE and functions as a critical immune-independent tumor suppressor. In patient samples, mouse models, and organoid systems, ciliated cells mounted a dual protective response to ovulation-associated genotoxic stress: intrinsic STING-driven apoptosis and extrinsic clearance of neighboring damaged secretory cells via TNFα secretion. This surveillance mechanism markedly limited DNA damage accumulation within the epithelial microenvironment. Crucially, although these mechanisms were vital for maintaining homeostasis and reducing genomic instability, they failed to affect p53-deficient precursor lesions as both the intrinsic and extrinsic proapoptotic processes relied on functional p53 signaling. These findings redefine ciliated cells as key gatekeepers of genome integrity rather than passive bystanders and implicate the early loss of STING-high ciliated cells as a pivotal event in HGSC initiation. Significance: STING-high ciliated fallopian tube cells function as immune-independent active guardians of genomic integrity whose loss creates a permissive niche for high-grade serous carcinoma initiation, which could inform prevention and treatment strategies.