Therapeutic targeting of interleukin-17C signaling in carcinogenesis of endometriosis

Endometriosis-associated ovarian carcinoma (EAOC) predominantly arises from the malignant transformation of endometriomas, yet the mechanism is incompletely defined. Spatial transcriptomic analysis of human specimens of normal endometrium, endometriomas, and EAOC identified interleukin-17C (IL-17C) signaling activation, with higher IL-17 receptor E (IL-17RE) expression in EAOC. Additionally, the IL-17C concentration was significantly increased in the peritoneal fluid of women with ovarian cancer. Using an endometriosis mouse model overexpressing IL-17RE, IL-17C levels were elevated in the peritoneal fluid. Furthermore, IL-17C knockout reduced the peritoneal fluid IL-17C concentration and inhibited ectopic lesion growth in endometriosis mice. In addition, the role of IL-17C signaling in promoting endometriosis carcinogenesis was investigated by blocking and modulating the IL-17C/IL-17RE pathway in human endometriotic epithelial cells, endometrial organoids, and ovarian endometriosis mice. These data identified IL-17C signaling as a driver of endometriosis carcinogenesis and propose IL-17C/IL-17RE as promising therapeutic targets, particularly for EAOC cases characterized by high IL-17C expression.