ArticleJournal of experimental & clinical cancer research : CR2025
Neutrophil-macrophage crosstalk via NETs-IL-17/VEGF/S100A9 axis promotes hepatocellular carcinoma progression.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Immunosuppressive roles of pericytes in cancer disease: insights from a systematic review and meta-analysis.Journal of translational medicine · 2026Pooled it
- Long-term polystyrene nanoplastics exposure aggravates retinal inflammation and photoreceptor degeneration through microglial SPP1 signaling and neutrophil extracellular traps formation.Journal of translational medicine · 2026Article
- The Molecular Network of Neutrophil Extracellular Traps in Hepatocellular Carcinoma: Biogenesis, Function, and Therapeutic Implications.Molecules (Basel, Switzerland) · 2026Review
- Chronic and non-canonical cGAS-STING activation: implications for health, disease, cancer, and emerging therapeutic opportunities.Apoptosis : an international journal on programmed cell death · 2026Review
- Identification of NETs and inflammation-related prognostic genes in breast cancer and PCR experimental validation.Frontiers in genetics · 2026Article
- Spatial immune niche remodeling of the neutrophil-macrophage axis inchronic liver disease.Frontiers in cell and developmental biology · 2026Review
- Inflammation in hepatocellular carcinoma progression: a "Single Wick, dual interwoven strands" regulatory framework.Frontiers in immunology · 2026Review
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Authors and funding
11 authors.
Funding
Abstract
backgroundTumor-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.
methodsBioinformatic 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.
resultsNETs 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 macrophages. Furthermore, IL-17 carried by NETs (NETs-IL-17) demonstrated strong predictive value for extrahepatic metastasis in HCC, with an area under the ROC curve (AUC) of 0.89.
conclusionsA positive feedback loop between neutrophils and macrophages via the NETs-IL-17/VEGF/S100A9 axis accelerates HCC progression and metastasis. More importantly, NETs-IL-17 exhibited potential as an alternative biomarker for predicting extrahepatic metastasis in HCC.
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