Agonist signaling drives neutrophil subpopulations to promote/inhibit colorectal cancer liver metastasis

Liver metastasis is a primary cause of death in colorectal cancer, yet the role of immune cells called neutrophils in this process remains complex. In this study, we identify three distinct neutrophil subtypes: anti-tumor high-density neutrophils, pro-tumor mature low-density neutrophils, and immature low-density neutrophils. Here we show that tumor-derived GM-CSF converts anti-tumor neutrophils into a pro-tumor state via the AKT-NF-κB-NFAT5 signaling axis. These activated neutrophils, when further stimulated by CXCR2 ligands, release web-like structures known as neutrophil extracellular traps which promote cancer spread by enhancing cancer cell growth, suppressing immune responses, and preparing the liver for metastasis. Importantly, we demonstrate that using antibodies depleting neutrophils or drugs inhibiting their pro-tumor activity effectively reduces liver metastasis in mice. Our work defines specific neutrophil subsets as key drivers of cancer progression and highlights their therapeutic potential in preventing metastatic spread.

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Publication Details

Journal
Nature Communications
Published
2025-12-17
DOI
https://doi.org/10.1038/s41467-025-67579-7
Citations
2
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
Field-Weighted Citation Impact
1.59
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article

Agonist signaling drives neutrophil subpopulations to promote/inhibit colorectal cancer liver metastasis

Zhuoqing Xu, Wenqing Feng, Han Gao, Zifeng Xu et al.
2 citations
Nature Communications
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
1.59
article

Agonist signaling drives neutrophil subpopulations to promote/inhibit colorectal cancer liver metastasis

Zhuoqing Xu, Wenqing Feng, Han Gao, Zifeng Xu, Jianting Huo, Aiguo Lu, Fangqian Chen, Yuchen Zhang, Wangyi Liu, Zeping Lv, Suyue Yu, Jingkun Zhao, Haoran Feng, Xi Cheng, Yaping Zong, Wenchang Li, Xiaohui Shen, Abudumaimaitijiang Tuersun
article en
2 citations

Abstract

Liver metastasis is a primary cause of death in colorectal cancer, yet the role of immune cells called neutrophils in this process remains complex. In this study, we identify three distinct neutrophil subtypes: anti-tumor high-density neutrophils, pro-tumor mature low-density neutrophils, and immature low-density neutrophils. Here we show that tumor-derived GM-CSF converts anti-tumor neutrophils into a pro-tumor state via the AKT-NF-κB-NFAT5 signaling axis. These activated neutrophils, when further stimulated by CXCR2 ligands, release web-like structures known as neutrophil extracellular traps which promote cancer spread by enhancing cancer cell growth, suppressing immune responses, and preparing the liver for metastasis. Importantly, we demonstrate that using antibodies depleting neutrophils or drugs inhibiting their pro-tumor activity effectively reduces liver metastasis in mice. Our work defines specific neutrophil subsets as key drivers of cancer progression and highlights their therapeutic potential in preventing metastatic spread.

Nature CommunicationsVol. 17(1)
Ruijin Hospital (CN), Shanghai Institute of Hematology (CN)
Openalex Percentile: Top 13%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
1.59
DOIOpen Access PDFOpenAlex
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