Neutrophil Extracellular Traps: From Mechanistic Insights to Therapeutic Targeting.

Neutrophils represent the most abundant leukocytes in circulation and serve to protect the host from infection. Paradoxically, they also contribute to cancer by releasing extracellular traps known as neutrophil extracellular traps (NETs). These structures exert opposing effects on tumors, either promoting progression or suppressing growth, depending on the specific context. However, a comprehensive framework reconciling these dual roles is lacking. NETs can be reconceptualised as multimodal signal processors within the tumor microenvironment, with a primary focus on cancer while acknowledging relevance to certain inflammatory and autoimmune conditions. NETs function through three interconnected modalities: (1) biomechanical scaffolds that remodel tissue architecture via integrin-focal adhesion kinase (FAK) mechanotransduction; (2) immunometabolic hubs that drive glycolytic reprogramming and immune suppression; and (3) signal-integration platforms that concentrate oncogenic cues for synergistic pathway activation. This systems-level perspective, orchestrated by nodes such as hypoxia-inducible factor 1-alpha and integrin-FAK, elucidates how microenvironmental inputs dictate NET phenotypic polarity. Furthermore, therapeutic implications are addressed, including biomarker-guided stratification, optimal intervention timing during the perioperative period, dormancy phase, immunotherapy combinations, and strategies to disrupt modal crosstalk while preserving essential host defence. Future priorities include resolving NET heterogeneity and developing localised delivery systems. This roadmap enhances precision targeting of NETs in oncology and other fields.