NETs in ovarian cancer progression: innovative nanoparticle-based therapeutic strategies
Ovarian cancer is an aggressive and heterogeneous malignancy characterized by genetic diversity, clonal evolution, and rapid development of therapeutic resistance, representing a major global clinical challenge. Neutrophils actively drive disease progression by fostering tumor growth, angiogenesis, immune evasion, and metastasis through the formation of neutrophil extracellular traps (NETs). NETs accelerate epithelial-to-mesenchymal transition (EMT), remodel the extracellular matrix (ECM), and prime pre-metastatic niches, creating a permissive environment for metastatic dissemination. Elevated NET levels correlate with advanced disease and poor prognosis, positioning them as powerful diagnostic and prognostic biomarkers. To exploit this vulnerability, we propose a multifunctional nanoparticle platform co-delivering GSK484, a selective anti-NETosis agent, alongside a potent cytotoxic drug. Engineered for tumor-selective targeting and pH-responsive release, this system dismantles the NET-rich tumor microenvironment while directly eradicating cancer cells, maximizing local efficacy and minimizing systemic toxicity. By simultaneously neutralizing the NET-modified niche and attacking tumor cells, this strategy has the potential to overcome chemoresistance, block metastatic spread, and enable precision-guided therapy. Implementation of this approach could refine patient stratification, enhance response rates, reduce recurrence, and translate into tangible survival benefits. This review highlights NETs as central orchestrators of ovarian cancer progression and presents a translationally actionable nanomedicine strategy poised to transform clinical outcomes in a malignancy long plagued by therapeutic failure.