Neutrophils drive vascular occlusion, tumour necrosis and metastasis

作者：José 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, Mikala Egeblad · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09278-3 · 被引用次数：75 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Cell Adhesion Molecules Research、S100 Proteins and Annexins

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. Neutrophils actively induce tumour necrosis, driving vascular occlusion, pleom...