Interferon Beta Drives Therapy Resistance in a Patient-Derived Model of High-Grade Serous Ovarian Cancer

ABSTRACT Cancer cell-autonomous type 1 interferon (IFN-1) production and signaling is frequently activated in response to DNA damage and has been associated with the development of therapy resistance in several cancer types. However, its cell-autonomous role in driving resistance in high-grade serous ovarian cancer (HGSOC), a disease defined by near-universal exposure to genotoxic therapy as frontline treatment, remains unclear. Specifically, whether IFN-1 functions in HGSOC as only a response to genotoxic stress or can independently act in driving resistance phenotypes has not been studied. Utilizing a syngeneic 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 the interferon-related DNA damage resistance signature (IRDS). Acute cisplatin treatment elicited dynamic, temporal IFN-1 signaling and responses in both sensitive and resistant cells, indicating a conserved stress response in resistant cells. Chronic, low-level exposure to exogenous IFNβ, in the absence of a DNA-damaging agent, was sufficient to phenocopy several features of chronic cisplatin driven resistance, including reduced therapeutic sensitivity, cell cycle arrest, and decreased proliferation. Notably, IFNβ driven resistance occurred without sustained IRDS or canonical interferon stimulated gene (ISG) induction, revealing alternative mechanisms for IFN-1 mediated therapy resistance. Together, these findings identify IFNβ as a functional driver of the development of resistance-associated phenotypes and highlight cell-autonomous IFN-1 signaling as a potential biomarker for resistance and a therapeutic target in platinum-resistant disease.