Senescent-Like Neutrophils Shape Angiogenic Immunosuppressive Niches in Colorectal Cancer Liver Metastasis
7 affiliations
- 1The First Affiliated Hospital of Sun Yat-sen University 1 Department of Liver Surgery, Center of Hepato-pancreato-biliary Surgery, , Guangzhou, China
- 2The First Affiliated Hospital, Sun Yat-sen University 2 Department of Oncology, , Guangzhou, China
- 3The First Affiliated Hospital, Sun Yat-sen University 3 Department of Gastrointestinal Surgery, , Guangzhou, China
- 4The First Affiliated Hospital, Sun Yat-sen University 4 Institute of Precision Medicine, , Guangzhou, China
- 5The First Affiliated Hospital, Sun Yat-sen University 5 Department of Gastroenterology and Hepatology, , Guangzhou, China
- 6The First Affiliated Hospital of Sun Yat-sen University 6 Department of Medical Statistics, Clinical Trials Unit, , Guangzhou, China
- 7The First Affiliated Hospital of Sun Yat-sen University 7 Cancer Center, , Guangzhou, China
Abstract
Neutrophils are major players in innate immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. In this study, using single-cell RNA sequencing and spatial-enhanced-resolution-omics sequencing, we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TAN) in CRLM. Our analysis reveals that a terminally differentiated protumor neutrophil subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes antitumor immunity and suppresses tumor growth. Our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM. SIGNIFICANCE: This study identifies a protumoral BHLHE40+ senescent-like neutrophil subset in CRLM that orchestrates vascular immunosuppressive niches to drive tumor progression, highlighting a potential target for neutrophil-specific therapeutic intervention. See related commentary by Droin and Garner, p. 1958.
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BibTeX
@article{chen2026senescentlike,
title = {{Senescent-Like Neutrophils Shape Angiogenic Immunosuppressive Niches in Colorectal Cancer Liver Metastasis}},
author = {Zhihang Chen and Xiaoxue Ren and Y M Zhang and Youmei Kang and Ye Yang and Yihang Xu and Qian Zhou and Changyi Liao and Qianwen Zeng and Xin Liu and 林壬璇 and Yu Yang and Feng Luo and Shunli Shen and Sui Peng and X. Li and Jianting Long and L Xu and Ming Kuang},
journal = {Cancer Discovery},
year = {2026},
month = may,
doi = {10.1158/2159-8290.cd-25-0820},
url = {https://doi.org/10.1158/2159-8290.cd-25-0820},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Senescent-Like Neutrophils Shape Angiogenic Immunosuppressive Niches in Colorectal Cancer Liver Metastasis
AU - Zhihang Chen
AU - Xiaoxue Ren
AU - Y M Zhang
AU - Youmei Kang
AU - Ye Yang
AU - Yihang Xu
AU - Qian Zhou
AU - Changyi Liao
AU - Qianwen Zeng
AU - Xin Liu
AU - 林壬璇
AU - Yu Yang
AU - Feng Luo
AU - Shunli Shen
AU - Sui Peng
AU - X. Li
AU - Jianting Long
AU - L Xu
AU - Ming Kuang
PY - 2026
DA - 2026/05/19
JO - Cancer Discovery
DO - 10.1158/2159-8290.cd-25-0820
UR - https://doi.org/10.1158/2159-8290.cd-25-0820
AB - Neutrophils are major players in innate immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. In this study, using single-cell RNA sequencing and spatial-enhanced-resolution-omics sequencing, we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TAN) in CRLM. Our analysis reveals that a terminally differentiated protumor neutrophil subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes antitumor immunity and suppresses tumor growth. Our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM. SIGNIFICANCE: This study identifies a protumoral BHLHE40+ senescent-like neutrophil subset in CRLM that orchestrates vascular immunosuppressive niches to drive tumor progression, highlighting a potential target for neutrophil-specific therapeutic intervention. See related commentary by Droin and Garner, p. 1958.
SN - 2159-8274
SN - 2159-8290
ER -