Interplay of replication stress response and immune microenvironment in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. Therapeutic options remain limited for patients lacking predictive biomarkers, particularly those with BRCA wild-type tumors or those who have acquired resistance to both PARP inhibitors and platinum-based chemotherapy. Replication stress, TP53 mutations, and genomic instability characterize HGSOC. The cellular response to replication stress is primarily mediated by checkpoint kinases; however, this mechanism is frequently impaired in tumor cells. Consequently, cancer cells become increasingly dependent on the replication stress response (RSR) pathway for survival, and susceptible to therapies targeting the ATR-CHK1-WEE1 axis-a key regulator of genomic integrity. Inhibition of these checkpoint kinases can disrupt cell cycle control, inducing mitotic catastrophe and subsequent cancer cell death. Another defining feature of HGSOC is its immunosuppressive tumor microenvironment (TME), which has limited the efficacy of immune checkpoint inhibitors. Emerging evidence suggests that inhibition of the RSR pathway may not only exploit intrinsic tumor vulnerabilities but also modulate the TME to enhance anti-tumor immune responses. This provides rationale for combination approaches integrating RSR pathway inhibitors with innovative immune checkpoint blockade (ICB). This review examines the mechanistic rationale and therapeutic potential of such combinations, drawing on both preclinical and clinical data.