The neutrophil-NET Axis in ovarian cancer: Drivers of tumor microenvironment remodeling and therapeutic resistance

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.