Roles of neutrophil extracellular traps in cancer immunotherapy resistance and therapeutic targeting

Resistance to cancer immunotherapy markedly limits clinical benefit, and neutrophil extracellular traps (NETs) have emerged as critical mediators in shaping the immunosuppressive tumor microenvironment. The molecular components of NETs, including cell-free DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histones (H3Cit)—have demonstrated significant clinical utility as diagnostic indicators and prognostic biomarkers for predicting disease progression and immunotherapy outcomes. Regulated by a complex network of tumor-derived signals and exosomes, NETs form dense physical barriers and promote T-cell exhaustion. This review elucidates the heterogeneity of NET formation and dissects the core mechanisms by which NETs mediate therapeutic resistance along two interrelated dimensions: spatial physical exclusion and biological functional modulation. Furthermore, we synthesize emerging strategies to target NETs—including inhibition of their formation, degradation of established barriers, and blockade of downstream interactions—with the aim of providing conceptual frameworks and translational directions for reshaping anti-tumor immunity and overcoming immunotherapy resistance.