Zendehdel Hoda, Esgandari Mahsa, Panahinia Paria, Fazeli Ramina, Etezadi Atoosa, Rahimi Sania
Gynecologist Oncologist, Department of Obstetrics and Gynecology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Department of Obstetrics and Gynecology, Medical Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Int Immunopharmacol. 2026 Jan 1;168(Pt 1):115826. doi: 10.1016/j.intimp.2025.115826. Epub 2025 Nov 10.
Ovarian cancer remains the most lethal gynecologic malignancy, characterized by profound molecular heterogeneity, immune evasion, and resistance to therapy. Despite surgical and chemotherapeutic advances, recurrence and omental metastasis persist, underscoring an incomplete understanding of the inflammatory circuits sustaining disease progression. Recent insights reveal that neutrophils are not passive responders but active architects of the ovarian tumor microenvironment (TME). Tumor-derived cytokines (IL-8, G-CSF, CXCL1/2) and metabolic cues such as hypoxia and lactate drive their polarization toward a pro-tumor phenotype and trigger NETosis-the release of chromatin webs decorated with histones and proteases. These neutrophil extracellular traps (NETs) remodel the TME by enhancing vascular permeability, supporting angiogenesis, and providing adhesive scaffolds for peritoneal implantation. Beyond their structural role, NETs promote immune escape by degrading chemokines essential for cytotoxic T-cell recruitment, engaging pattern-recognition receptors, and activating NF-κB- and STAT3-dependent pro-survival signaling in tumor and stromal cells. This dual function-linking innate immune dysregulation with metastatic competence-positions NETosis as a pivotal determinant of ovarian cancer progression. This review integrates emerging data on neutrophil-tumor crosstalk, delineating how ovarian cancer cells exploit NET-related pathways, including PAD4 activation, ROS amplification, and cytokine feedback loops, to construct a pro-metastatic niche within the omentum. Finally, we highlight the therapeutic promise of targeting NETosis through PAD4 inhibitors, DNase-based strategies, and immunomodulatory interventions aimed at reprogramming the tumor-neutrophil axis. By decoding this neutrophil-NET-tumor network, we propose a paradigm in which dismantling NETosis could limit metastasis, restore immune surveillance, and improve therapeutic sensitivity in ovarian cancer.
卵巢癌仍然是最致命的妇科恶性肿瘤，其特征是存在深刻的分子异质性、免疫逃逸和对治疗的抗性。尽管手术和化疗取得了进展，但复发和网膜转移仍然存在，这突出表明我们对维持疾病进展的炎症回路理解不全面。最近的见解表明，中性粒细胞并非被动反应者，而是卵巢肿瘤微环境（TME）的积极构建者。肿瘤衍生的细胞因子（IL-8、G-CSF、CXCL1/2）以及诸如缺氧和乳酸等代谢信号促使它们向促肿瘤表型极化，并触发中性粒细胞胞外陷阱形成——释放由组蛋白和蛋白酶修饰的染色质网。这些中性粒细胞胞外陷阱（NETs）通过增强血管通透性、支持血管生成以及为腹膜植入提供粘附支架来重塑TME。除了其结构作用外，NETs还通过降解细胞毒性T细胞募集所必需的趋化因子、参与模式识别受体以及激活肿瘤和基质细胞中依赖NF-κB和STAT3的促生存信号来促进免疫逃逸。这种将先天性免疫失调与转移能力联系起来的双重功能使中性粒细胞胞外陷阱形成成为卵巢癌进展的关键决定因素。本综述整合了关于中性粒细胞与肿瘤相互作用的新数据，阐述了卵巢癌细胞如何利用与NET相关的途径，包括瓜氨酸化蛋白水解酶4（PAD4）激活、活性氧（ROS）放大和细胞因子反馈回路，在网膜内构建促转移微环境。最后，我们强调了通过PAD4抑制剂、基于脱氧核糖核酸酶的策略以及旨在重新编程肿瘤-中性粒细胞轴的免疫调节干预措施来靶向中性粒细胞胞外陷阱形成的治疗前景。通过解读这个中性粒细胞-NET-肿瘤网络，我们提出了一种模式，即消除中性粒细胞胞外陷阱形成可能会限制转移、恢复免疫监视并提高卵巢癌的治疗敏感性。
