Neutrophil extracellular traps in the tumor microenvironment, metastasis, therapy, and beyond: advances, challenges, and perspectives

Abstract Neutrophil extracellular traps (NETs), the DNA-protein structures released by neutrophils within the tumor microenvironment (TME), play a role in cancer that extends far beyond their traditional antimicrobial function. Specifically, NETs exert multifaceted and context-dependent effects on tumor progression, metastasis, immune regulation, and therapeutic response, showing their robust activity in shaping the complex landscape of tumor biology. This review systematically elucidates how NETs promote tumorigenesis by inducing DNA damage and epithelial-mesenchymal transition (EMT), and drive metastatic spread through mechanisms such as trapping circulating tumor cells, remodeling the pre-metastatic microenvironment, and reactivating dormant cells. Concurrently, NETs shape an immunosuppressive TME by modulating T cells, NK cells, and macrophages, while mediating resistance to chemotherapy, radiotherapy, and immunotherapy. Based on these mechanisms, targeting NET formation (such as inhibiting PAD4 or NE) or degrading their structures (such as using DNase I) has emerged as a potential strategy to enhance the efficacy of existing therapies. Therefore, deepening the understanding of the multifunctional regulatory networks underlying NETs within the TME holds significant implications for developing novel precision cancer therapies.