Neutrophil-macrophage crosstalk via NETs–IL-17/VEGF/S100A9 axis promotes hepatocellular carcinoma progression

作者：Rong Wu, Rui Wu, Xuehua Kong, Xuanyi Wang, Yaqian Duan, Shiyu Cao, Shan Yu, Yuqing Zhao, Shue Li, Jingying Zhou, Liang Duan · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03618-x · 被引用次数：9 · 研究领域：Immune cells in cancer、Ferroptosis and cancer prognosis、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

BACKGROUND: Tumor-associated neutrophils and macrophages are key components of the hepatocellular carcinoma (HCC) microenvironment. However, the interplay between them and its contribution to HCC progression remain unclear. METHODS: Bioinformatic analysis of TCGA datasets and clinical HCC samples was used to evaluate neutrophil extracellular trap (NETs) levels and macrophage polarization. Co-culture of neutrophils, macrophages, and HCC cells, along with molecular analysis and in vivo mouse models, were employed to dissect the mechanisms underlying NETs-mediated macrophage reprogramming and tumor progression. RESULTS: NETs were significantly elevated in HCC patients, particularly in advanced and metastatic stages, which were positively correlated with intrahepatic M2 macrophage infiltration and M2d subset-associated cytokines in blood. In vitro, NETs promoted M2d polarization in the presence of HCC cells via IL-17R/NF-κB signaling activated by IL-17 carried within NETs, which subsequently enhanced angiogenesis, migration, invasion, and epithelial-mesenchymal transition; these effects were partially reversed by IL-17R inhibition. In vivo, NETs-induced M2d polarization accelerated tumor growth, angiogenesis, and metastasis, whereas IL-17R blockade attenuated these pro-tumor effects. Moreover, M2d macrophages indirectly promoted NETs formation by upregulating HCC cell-derived S100A9 through VEGF-NF-κB signaling, establishing a positive feedback loop between neutrophils and macrop...