Targeting neutrophil extracellular traps in non‑small cell lung cancer metastasis: From context‑dependent mechanisms to precision therapeutics (Review)

The high metastatic propensity of non‑small cell lung cancer (NSCLC) remains a major therapeutic challenge. Neutrophil extracellular traps (NETs) are dynamic components of the tumor microenvironment that can promote tumor‑cell adhesion, extravasation, inflammatory signaling, metabolic immunosuppression and treatment resistance. However, their biological effects are not uniformly pro‑tumorigenic: NET composition, neutrophil state, tumor histology, driver genotype, disease stage, treatment exposure, and host immune context may determine whether NETs exert predominantly pro‑metastatic, immunoregulatory, or direct cytotoxic effects. In the present review, the evidence was organized according to a translational sequence from mechanism to biomarker, therapeutic intervention, and precision stratification. Evidence obtained in NSCLC was further distinguished from findings derived from other tumor types. It was emphasized that antitumor NET activity remains biologically plausible but insufficiently characterized in human NSCLC in vivo. Therapeutic development is currently at different stages: Selective PAD4 inhibition remains preclinical, whereas NET‑adjacent CXCR1/2 blockade has entered clinical trials in advanced NSCLC; DNase I has clinical experience mainly in non‑oncologic settings and has not established efficacy as a NET‑targeted anticancer therapy. A stage‑ and context‑dependent therapeutic window was therefore proposed, in which short‑duration or locally enriched NET modulation is considered only after assessment of NET burden, infection risk, tumor genotype, disease stage and treatment context. A multidimensional biomarker framework integrating NET markers, neutrophil state, circulating tumor DNA‑defined tumor genotype, immune contexture and treatment exposure may provide a more clinically actionable basis for patient selection.