Neutrophil Extracellular Traps in Cancer Progression and Metastasis

Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin studded with antimicrobial proteins, released by activated neutrophils. Although originally identified as a defence mechanism against pathogens, NETs have emerged as pivotal players in cancer biology. Within the tumour microenvironment, NETs contribute to multiple facets of tumour progression: they can immobilise circulating tumour cells, facilitate their adhesion to distant endothelium and thereby promote metastatic seeding; they engender a pro-inflammatory milieu that supports tumour cell survival and proliferation; and they interact with stromal and immune cells to dysregulate local immune surveillance. In some contexts, NET-associated enzymes and cytokines exacerbate coagulation cascades, increasing the risk of cancer-associated thrombosis. NET formation, or NETosis, can be triggered by tumour-derived factors—such as cytokines, exosomes and lipid metabolites—which in turn amplify neutrophil recruitment and activation. Conversely, metabolic pathways within both neutrophils and tumour cells influence the propensity to undergo NETosis. The global significance of NETs in oncology is underscored by their detection in patient blood and tissue samples across diverse malignancies and by correlations between NET markers and poor clinical outcomes. Consequently, interventions targeting NET formation or promoting NET degradation are under active investigation as adjunctive therapies to limit metastasis and thrombotic complications in cancer patients.

Research from Nature Portfolio

Recent studies have elucidated novel mechanisms by which tumour cell death and metabolic reprogramming modulate NET-dependent metastasis. In one investigation, apoptotic tumour cells were shown to undergo nuclear expulsion, generating extracellular DNA–protein complexes enriched in ligands for the receptor for advanced glycation end-products (RAGE). Engagement of RAGE on neighbouring viable tumour cells activated signalling cascades that enhanced metastatic outgrowth, revealing how dying cells can paradoxically accelerate dissemination of their survivors. In colorectal cancer, a lipid-metabolism enzyme was identified that inhibits the peroxisomal synthesis of ether lipids, reducing interleukin-8 expression, neutrophil recruitment and subsequent NET formation. Loss or downregulation of this enzyme correlated with poorer patient prognosis, highlighting a metabolic checkpoint of NET-mediated tumour progression. Together, these findings implicate both apoptotic cell–derived nuclear material and tumour lipid metabolism as key regulators of NET-driven metastasis, offering potential targets for therapeutic intervention.

Neutrophil Extracellular Traps in Cancer Progression and Metastasis publication trend

The graph below shows the total number of articles in neutrophil extracellular traps in cancer progression and metastasis across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil extracellular traps (NETs): Fibrous networks of decondensed chromatin and granule proteins extruded by activated neutrophils.

NETosis: The regulated process by which neutrophils release NETs, encompassing chromatin decondensation and cell membrane rupture.

Receptor for advanced glycation end-products (RAGE): A cell-surface receptor that binds diverse ligands, including NET-associated proteins, to trigger pro-metastatic signalling.

Tumour microenvironment: The complex milieu of cancer cells, stromal cells, immune cells and extracellular matrix that orchestrates tumour progression and response to therapy.

References

1. The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Frontiers in Immunology (2020).
2. Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis. Scientific Reports (2017).
3. Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway. Nature Cancer (2023).
4. The lipid-metabolism enzyme ECI2 reduces neutrophil extracellular traps formation for colorectal cancer suppression. Nature Communications (2024).
5. The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer. Immunity (2023).
6. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. Journal of Hematology & Oncology (2020).