Nanodrug-based modulation of platelet–leukocyte interactions in ovarian cancer: a new frontier in targeted therapy

Ovarian cancer (OC) remains a leading cause of gynecologic cancer mortality due to its biological heterogeneity, late-stage diagnosis, and resistance to conventional therapies. The tumor microenvironment (TME) plays a critical role in driving disease progression, with pathological interactions between activated platelets and leukocytes significantly contributing to immune evasion, metastasis, and thromboinflammation. Platelet-derived P-selectin facilitates platelet–neutrophil aggregation, leading to the formation of neutrophil extracellular traps (NETs) via NETosis, which further promotes tumor growth and thrombotic complications. In addition, platelet-secreted TGF-β1 enhances an immunosuppressive environment, inducing epithelial-to-mesenchymal transition (EMT) and skewing immune cell polarization toward tumor-promoting phenotypes. In this review, we explore the mechanistic role of platelet–leukocyte interactions in OC progression and examine current pharmacologic challenges in targeting these interactions. We then propose a novel therapeutic strategy involving pH-responsive nanoparticles co-loaded with anti-platelet agents and doxorubicin, designed to selectively release their payload within the acidic TME. This nanodrug aims to inhibit platelet activation, reduce NET formation, and enhance local cytotoxic efficacy while minimizing systemic toxicity and bleeding risk—common challenges with conventional therapies. By integrating principles from tumor immunology, hemostasis, and nanomedicine, our strategy offers a promising, multi-targeted approach to OC therapy. We advocate for further preclinical and clinical studies to assess the potential of this nanodrug in overcoming immune resistance and thromboinflammatory complications in advanced ovarian cancer.