CCNE1 overexpression drives a cGAS–STING-dependent interferon response and sensitizes HRD-positive ovarian cancer to immune checkpoint blockade
Abstract
Abstract Background Homologous recombination deficiency (HRD) in high-grade serous ovarian carcinoma (HGSOC) canonically dictates sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors. Although CCNE1 amplification is generally mutually exclusive with BRCA mutations, CCNE1 overexpression paradoxically co-occurs with HRD in approximately 4%–12% of cases. We investigated the clinical impact and immune landscape of this concurrent phenotype to uncover novel therapeutic vulnerabilities. Methods We stratified HGSOC patients from independent cohorts based on CCNE1 expression and HRD status to evaluate survival and therapeutic response. The tumor immune microenvironment was characterized using single-cell RNA sequencing and multiplex immunofluorescence. Mechanistic investigations were conducted using Brca1-deficient ID8 murine models, and the efficacy of anti-PD-1 therapy was assessed in vivo and ex vivo using the patient-derived tumor fragments (PDTFs) platform. Results Clinically, CCNE1 overexpression abrogated the survival advantage typically conferred by HRD. Biologically, however, CCNE1high/HRD tumors exhibited a highly inflamed microenvironment characterized by robust infiltration of polyfunctional CD8+ T cells and CXCL9+ tumor-associated macrophages. Mechanistically, CCNE1 overexpression in an HRD background exacerbated replication stress and reactive oxygen species (ROS) accumulation, leading to cytosolic DNA leakage. This triggered a cGAS–STING-dependent type I interferon response, which was reversed by STING inhibition or ROS scavengers. Consequently, CCNE1high/HRD tumors demonstrated profound sensitivity to anti-PD-1 treatment in syngeneic mouse models and the HGSOC PDTFs platform. Conclusions CCNE1 overexpression in HRD ovarian cancer drives cGAS–STING-dependent inflammation, transforming genotoxin-refractory tumors into highly vulnerable targets for anti-PD-1 therapy.