The dual role of IFI27 in ovarian cancer: cell-autonomous pro-apoptotic effects versus non-cell-autonomous tumor-promoting functions mediated by KGN cells

Background Ovarian cancer progression is driven by complex interactions between malignant cells and the tumor microenvironment. Interferon-induced protein 27 (IFI27) has been implicated in cancer biology, but its cell type-specific functions in ovarian cancer remain poorly understood. Methods Human single-cell and bulk transcriptomic data were analyzed to characterize IFI27 expression patterns, intercellular communication networks, and survival associations. Functional roles of IFI27 were investigated using ovarian cancer cell lines (A2780 and SKOV3), the granulosa tumor-derived cell line KGN, transwell co-culture, pharmacological rescue, and orthotopic humanized mouse models. Clinical relevance was assessed by immunohistochemical analysis of ovarian serous carcinoma tissues. Results Single-cell analysis revealed extensive bidirectional communication between ovarian cancer cells and cumulus granulosa cells, and integrated transcriptomic analyses linked higher IFI27 expression to favorable overall survival. IFI27 expression was elevated in ovarian cancer tissues compared with adjacent tissues. In ovarian cancer cells, IFI27 overexpression induced mitochondrial dysfunction, lipid metabolic imbalance, oxidative stress, inflammatory activation, and apoptosis, accompanied by reduced cell viability. C75 partially attenuated lipid accumulation and mitochondrial depolarization, whereas N-acetylcysteine partially reduced apoptosis. In contrast, IFI27 overexpression in KGN cells increased viability and reduced apoptosis in co-cultured ovarian cancer cells. In vivo, systemic IFI27 overexpression reduced tumor burden, promoted tumor-tissue apoptosis, and reshaped the tumor immune-cell composition. Conclusions IFI27 overexpression in cancer cells suppresses their survival, whereas overexpression in KGN cells promotes the survival of co-cultured cancer cells. These findings provide a rationale for cell type-specific therapeutic targeting of IFI27. Clinical trial number Not applicable.