Sticky situation, strategic strike: Targeting neutrophil extracellular trap-work in cancer

Abstract

Neutrophil extracellular traps (NETs), once recognised solely as antimicrobial defenders, have emerged as key, yet paradoxical, players in the complex theatre of cancer. These intricate webs of DNA decorated with cytotoxic granule proteins, ejected by activated or dying neutrophils via NETosis, are now implicated in nearly every stage of tumour progression. Recent advances, as comprehensively reviewed by Wang et al. in Clinical and Translational Medicine, reveal that NETs are dynamically regulated by the tumour microenvironment (TME) and exhibit context-dependent pro- or anti-tumour effects.¹ Cytokines (IL-8, G-CSF, TNF-α), tumour-derived extracellular vesicles (EVs), platelets, complement factors, and even extracellular matrix (ECM) aberrations can trigger NETosis. Once formed, NETs wield a double-edged sword: their DNA scaffolds, proteases (NE, MPO), histones, and associated proteins can directly fuel tumour cell proliferation, invasion, epithelial–mesenchymal transition (EMT), and awakening of dormant cells, whilst simultaneously establishing physical traps for circulating tumour cells (CTCs) in distant organs, facilitating metastasis.² They contribute to a pro-thrombotic state, therapy resistance (particularly to chemotherapy and immunotherapy), and immunosuppression by excluding cytotoxic T cells. Conversely, under specific contexts, NETs may exert anti-tumour cytotoxicity. Clinically, NETs components (e.g., citrullinated histone H3 [CitH3], cell-free DNA [cfDNA]) serve as diagnostic/prognostic biomarkers, whilst therapeutic strategies targeting NET formation (e.g., PAD4 inhibitors) or degradation (e.g., DNase I) show promise in preclinical models. Despite progress, key challenges—including NETs heterogeneity, detection standardisation, and therapeutic specificity—remain unresolved.

The burgeoning field of NETs in oncology holds immense potential, but significant challenges and exciting opportunities lie ahead. Future studies should prioritise (Figure 1).

The intricate dance between NETs and cancer is far from fully choreographed. Whilst their detrimental roles in promoting metastasis, thrombosis, immunosuppression, and therapy resistance are increasingly clear, harnessing their biology offers unprecedented opportunities. The future lies in moving beyond broad inhibition towards precision targeting—understanding the nuances of NET heterogeneity, context-specific functions, and their intricate interactions within the TME. Overcoming technical hurdles in detection and drug delivery, rigorously validating biomarkers, and designing intelligent clinical trials combining NET-targeting strategies with established and emerging therapies are critical next steps. Success in this endeavour promises not only deeper biological insights but also the development of novel diagnostic tools and therapeutic arsenals to disrupt the dark side of NETs, ultimately improving outcomes for cancer patients burdened by their tangled webs. The journey from understanding NET mechanisms to translating them into effective medicine is complex, but the potential rewards for conquering metastasis and treatment resistance make it a compelling frontier in oncology.

Bo Cao wrote the initial draft of this manuscript. Ting La and Bo Cao reviewed the manuscript.

The authors declare no conflicts of interest.

This work was supported by the Natural Science Basic Research Program of Shaanxi Province, China [2023-JC-QN-0858] and the National Natural Science Foundation of China [82372638].

Not applicable.