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Background <p>High-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-dose hydroxyurea (LDHU) promotes a unique ATR-independent moderate replication stress response with potent anti-tumour effects. The ability of this approach to reprogram the tumour immune microenvironment (TIME) to overcome the immunosuppression and promote an anti-tumour immune response in HGSOC is the focus of this study.</p> Methods <p>We investigated the therapeutic potential of CHK1i+LDHU in established HGSOC cell cultures, fresh tumour cell explants from HGSOC patient ascites, and syngeneic mouse models, assessing tumour cell killing, immunogenic cell death, pro-inflammatory cytokine/chemokine expression, and anti-tumour immune responses.</p> Results <p>CHK1i+LDHU effectively killed ovarian cancer cells regardless of prior chemotherapy responses, <i>BRCA2</i> mutation and homologous recombination repair status in vitro. In vivo, treatment significantly reduced tumour burden and ascites accumulation. CHK1i+LDHU enhanced expression of pro-inflammatory cytokines/chemokines and triggered immunogenic cell death in tumour. In syngeneic models, treatment promoted CD8<sup>+</sup> cytotoxic T cell-dependent anti-tumour responses and reduced immunosuppressive signalling within the TIME.</p> Conclusions <p>CHK1i+LDHU is a promising therapy for chemotherapy-resistant HGSOC, combining direct cytotoxic effects with reprogramming the TIME to reduce immunosuppression and activate a CD8<sup>+</sup> T cell-dependent anti-tumour response.</p>

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Using targeted therapy to promote a pro-inflammatory tumour microenvironment and anti-tumour immune response in high grade serous ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月7日

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  • Zhen Zeng,
  • Anastasia Gandini,
  • Rituparna Bhatt,
  • Martina Proctor,
  • Nicole-Lisa Li-Ann Goh,
  • Shivam Vora,
  • Thomas P. Walsh,
  • Sherry Y. Wu,
  • Kaltin Ferguson,
  • Jermaine I. Coward,
  • Snehlata Kumari,
  • Nikolas K. Haass,
  • James W. Wells,
  • Janet Hardy,
  • Lewis Perrin,
  • Yaowu He,
  • John D. Hooper,
  • Gwo-Yaw Ho,
  • Jazmina L. Gonzalez Cruz,
  • Brian Gabrielli

摘要

Background

High-grade serous ovarian cancer (HGSOC) is characterized by elevated replication stress and an immunosuppressive microenvironment. A synergistic combination of checkpoint kinase 1 inhibitor (CHK1i) with low-dose hydroxyurea (LDHU) promotes a unique ATR-independent moderate replication stress response with potent anti-tumour effects. The ability of this approach to reprogram the tumour immune microenvironment (TIME) to overcome the immunosuppression and promote an anti-tumour immune response in HGSOC is the focus of this study.

Methods

We investigated the therapeutic potential of CHK1i+LDHU in established HGSOC cell cultures, fresh tumour cell explants from HGSOC patient ascites, and syngeneic mouse models, assessing tumour cell killing, immunogenic cell death, pro-inflammatory cytokine/chemokine expression, and anti-tumour immune responses.

Results

CHK1i+LDHU effectively killed ovarian cancer cells regardless of prior chemotherapy responses, BRCA2 mutation and homologous recombination repair status in vitro. In vivo, treatment significantly reduced tumour burden and ascites accumulation. CHK1i+LDHU enhanced expression of pro-inflammatory cytokines/chemokines and triggered immunogenic cell death in tumour. In syngeneic models, treatment promoted CD8+ cytotoxic T cell-dependent anti-tumour responses and reduced immunosuppressive signalling within the TIME.

Conclusions

CHK1i+LDHU is a promising therapy for chemotherapy-resistant HGSOC, combining direct cytotoxic effects with reprogramming the TIME to reduce immunosuppression and activate a CD8+ T cell-dependent anti-tumour response.