Ovarian cancer, neutrophil hitchhiking, and NETs: unraveling their role in pathogenesis and management.

Abstract

Ovarian cancer is the most lethal gynecologic malignancy, driven by extensive genetic heterogeneity, clonal evolution, and resistance to therapy. Despite advances in treatment, recurrence remains common, highlighting the urgent need for novel therapeutic strategies. Neutrophil extracellular traps (NETs)-web-like DNA-protein complexes released during NETosis-have recently emerged as key facilitators of tumor progression across multiple cancers. However, their role in ovarian cancer remains underexplored. NETs contribute to metastasis, angiogenesis, immune evasion, and chemoresistance, creating a pro-tumorigenic microenvironment. This review identifies critical knowledge gaps in NET-mediated mechanisms in ovarian cancer and introduces, for the first time in this context, the concept of neutrophil hitchhiking, whereby circulating tumor cells exploit neutrophils to enhance metastatic dissemination. We examine molecular pathways driving NETosis and their influence on the tumor microenvironment, highlighting how NET-targeted therapies-including NETosis inhibitors and immune modulators-offer promising avenues to suppress metastasis, restore immune surveillance, and improve treatment outcomes. By illuminating this underexplored axis of neutrophil-tumor interaction, we aim to stimulate research and therapeutic development that could transform ovarian cancer management.