Neutrophil extracellular traps enhance platinum resistance in ovarian cancer via SHP-1 activation

Platinum resistance continues to be a major therapeutic challenge in ovarian cancer, driving disease recurrence and limiting patient survival. In this study, we identify a significant enrichment of neutrophil extracellular traps (NETs) within the tumor microenvironment of platinum-resistant ovarian tumors. These NETs actively contribute to malignant progression by promoting epithelial-mesenchymal transition and fostering chemotherapy resistance. Mechanistically, we demonstrate that NETs drive chemoresistance through the unexpected activation of SHP-1. Although traditionally recognized as a tumor suppressor, SHP-1 assumes an oncogenic function in this context. Specifically, NETs trigger TGF-β signaling, resulting in Smad2 phosphorylation, which subsequently promotes both the enzymatic activation and nuclear translocation of SHP-1. Once in the nucleus, SHP-1 enhances RNA polymerase II-mediated transcription and nucleotide excision repair, ultimately enabling cancer cells to evade cisplatin-induced cytotoxicity. Our in vivo experiments corroborate these findings that elevated NETs levels exhibit poor response to cisplatin, while pharmacological inhibition of NETs effectively restores drug sensitivity. This study not only advances our understanding of microenvironment-driven drug resistance but also highlights the therapeutic potential of targeting the NETs/SHP-1 axis to overcome platinum resistance in ovarian cancer.