Abstract
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. Plateletderived
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.