Neutrophils drive vascular occlusion, tumour necrosis and metastasis

Jose M. Adrover (), Xiao Han, Lijuan Sun, Takeo Fujii, Nicole Sivetz, Juliane Daßler-Plenker, Clary Evans, Jessica Peters, Xue-Yan He, Courtney D. Cannon, Won Jin Ho, George Raptis, R. Scott Powers and Mikala Egeblad ()
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Jose M. Adrover: Cold Spring Harbor Laboratory
Xiao Han: Cold Spring Harbor Laboratory
Lijuan Sun: Cold Spring Harbor Laboratory
Takeo Fujii: Cold Spring Harbor Laboratory
Nicole Sivetz: Cold Spring Harbor Laboratory
Juliane Daßler-Plenker: Cold Spring Harbor Laboratory
Clary Evans: Cold Spring Harbor Laboratory
Jessica Peters: Northwell Health Cancer Institute
Xue-Yan He: Cold Spring Harbor Laboratory
Courtney D. Cannon: Johns Hopkins University School of Medicine
Won Jin Ho: Johns Hopkins University School of Medicine
George Raptis: Northwell Health Cancer Institute
R. Scott Powers: Stony Brook University
Mikala Egeblad: Cold Spring Harbor Laboratory

Nature, 2025, vol. 645, issue 8080, 484-495

Abstract: Abstract Tumour necrosis is associated with poor prognosis in cancer1,2 and is thought to occur passively when tumour growth outpaces nutrient supply. Here we report, however, that neutrophils actively induce tumour necrosis. In multiple cancer mouse models, we found a tumour-elicited Ly6GHighLy6CLow neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6GHighLy6CHigh neutrophils. The presence of these ‘vascular-restricted’ neutrophils correlated with the appearance of a ‘pleomorphic’ necrotic architecture in mice. In tumours with pleomorphic necrosis, we found intravascular aggregates of neutrophils and NETs that caused occlusion of the tumour vasculature, driving hypoxia and necrosis of downstream vascular beds. Furthermore, we found that cancer cells adjacent to these necrotic regions (that is, in ‘perinecrotic’ areas) underwent epithelial-to-mesenchymal transition, explaining the paradoxical metastasis-enhancing effect of tumour necrosis. Blocking NET formation genetically or pharmacologically reduced the extent of tumour necrosis and lung metastasis. Thus, by showing that NETs drive vascular occlusion, pleomorphic necrosis and metastasis, we demonstrate that tumour necrosis is not necessarily a passive byproduct of tumour growth and that it can be blocked to reduce metastatic spread.

Date: 2025
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DOI: 10.1038/s41586-025-09278-3

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