Neutrophil extracellular traps in tumor microenvironment for radiotherapy: friend or foe?

Neutrophil extracellular traps (NETs) are chromatin-protein complexes released by neutrophils that have dual roles in the tumor microenvironment (TME), participating in anti-tumor immunity and driving malignant progression by promoting tumor proliferation, metastasis, and immune escape. Radiotherapy (RT) exerts anticancer effects by inducing DNA damage and microenvironmental remodeling, but the inflammatory response it triggers can activate the formation of NETs, which exacerbate radioresistance by degrading the extracellular matrix, encapsulating circulating tumor cells, inhibiting CD8+ T-cell infiltration, and promoting distant tumor metastasis. Meanwhile, NETs may act in concert with neutrophils to indirectly enhance radiotherapy efficacy by releasing reactive oxygen species (ROS) and promoting activation and recruitment of tumor-specific T cells. Hypoxia, inflammatory factors, damage-associated molecular patterns (DAMPs), and microbial metabolites in the TME affect radiotherapy outcomes by regulating NET formation. Targeting NETs in combination with radiotherapy reverses immunosuppression and enhances anti-tumoral effects. The functional heterogeneity of NETs subtypes and their spatial and temporal dynamics need to be analyzed in order to optimize individualized treatment strategies.