REVIEW article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1638964
This article is part of the Research TopicTipping the Balance: DNA Replication and Repair Vulnerabilities in CancerView all 4 articles
Interplay of Replication Stress Response and Immune Microenvironment in High-Grade Serous Ovarian Cancer
Provisionally accepted
- 1Princess Margaret Hospital Cancer Centre, Toronto, Canada
- 2University Health Network, Toronto, Canada
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High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy.Therapeutic options remain limited for patients lacking predictive biomarkers, particularly Deleted: Immune Microenvironment and Deleted: 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 1checkpoint 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 immune checkpoint blockade (ICB), such as anti-PD-(L)1 therapies.This review examines the mechanistic rationale and therapeutic potential of such combinations, drawing on both preclinical and clinical data.
Keywords: TME (tumor microenvironment), replication stress, HGSOC, Wee1, Chk1, ATR, Immunotherapy, PDL1 inhibitors
Received: 31 May 2025; Accepted: 18 Aug 2025.
Copyright: © 2025 Venegas and Lheureux. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Stephanie Lheureux, University Health Network, Toronto, Canada
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