Heliang Li, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xinyan Liang, Linxi Xu, Jiang Li, Xiaoming Zhong, Xu Liu, Zhou Liu, Xinyu Yang, Yunyi Zhang, Shun Wang, Erwei Song, Man Nie, Linbin Yang
Neutrophil extracellular traps (NETs) are associated with cancer progression; however, the functional role and clinical importance of NET-DNA in therapeutic resistance remain unclear. Here, we show that chemotherapy and radiotherapy provoke NET-DNA formation in primary tumor and metastatic organs in breast cancer patients and mouse models, and the level of NET-DNA correlates with treatment resistance. Mechanistically, the cathepsin C in tumor debris generated by anticancer therapy is phagocytosed by macrophages and drives CXCL1/2 and complement factor B production via activating the TLR4/NF-κB signaling pathway, subsequently promoting NETosis and impairing therapeutic efficacy. Importantly, we demonstrate that NET-DNA sensor CCDC25 is indispensable in NET-mediated treatment resistance by inducing cancer cell epithelial-mesenchymal transition via pyruvate kinase isoform M2-mediated STAT3 phosphorylation. Clinically, tumoral CCDC25 abundance is closely associated with poor prognosis in patients who underwent chemotherapy. Overall, our data reveal the mechanism of NET formation and elucidate the interaction of NET-CCDC25 in therapy resistance, highlighting CCDC25 as an appealing target for anticancer interventions.