Type 1 interferon (IFN‐1) production and signaling are frequently activated in response to DNA damage and have been associated with the development of therapy resistance in cancer. However, the cell‐autonomous role of IFN‐1 in driving resistance in high‐grade serous ovarian cancer (HGSOC) remains unclear. Specifically, whether IFN‐1 functions in HGSOC as solely a response to genotoxic stress due to genotoxic therapy as frontline treatment, or can independently act in driving resistance phenotypes, has not been studied. Utilizing a patient‐derived model of cisplatin‐sensitive (SE) and ‐resistant (CR) HGSOC, we demonstrate that chronic cisplatin exposure is associated with enrichment of IFN‐1 signaling and an interferon‐related DNA damage resistance signature. Acute cisplatin treatment elicited dynamic IFN‐1 signaling in both SE and CR cells, indicating a conserved stress response. However, chronic, low‐level exposure to exogenous IFNβ, without a DNA‐damaging agent, phenocopied several features of chronic cisplatin‐driven resistance, including reduced therapeutic sensitivity and decreased proliferation. Together, these findings identify IFNβ as a driver of resistance‐associated phenotypes and highlight cell‐autonomous IFN‐1 signaling as a potential biomarker for resistance and therapeutic target in platinum‐resistant disease.
Conant et al. (2026) studied this question.