Volume 35, No 8, Aug 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 8, August 2025: 588-606

ORIGINAL ARTICLES

Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression

Wei Liu^1,† , Tao Shi^2,3,† , Chun Lu¹ , Keying Che² , Zijian Zhang¹ , Yuting Luo² , Daniel Hirschhorn^3,4 , Hanbing Wang² , Shaorui Liu⁵ , Yan Wang⁵ , Shuang Liu¹ , Haiqiao Sun¹ , Jun Lu⁶ , Yuan Liu⁶ , Dongquan Shi⁶ , Shuai Ding⁷ , Heping Xu⁵ , Liaoxun Lu⁸ , Jianming Xu , Jun Xin⁹ , Yinming Liang^10,11,* , Taha Merghoub^3,4 , Jia Wei^2,12,13,14 , Yan Li^1,15,16

¹National Resource Center for Mutant Mice and MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
²Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
³Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
⁴Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA
⁵Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
⁶State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
⁷Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
⁸Laboratory of Genetic Regulators in the Immune System School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
⁹GemPharmatech Co., Ltd., Jiangbei New Area, Nanjing, Jiangsu, China
¹⁰Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China
¹¹Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China
¹²State Key Laboratory of Pharmaceutical Biotechnology, School of life Sciences, Nanjing University, Nanjing, Jiangsu, China
¹³Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, Jiangsu, China
¹⁴Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
¹⁵Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing, Jiangsu, China
¹⁶Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi, Jiangsu, China
^†These authors contributed equally: Wei Liu, Tao Shi
Correspondence: Yinming Liang(yinming.liang@gris.org.cn)

Tumor-infiltrating neutrophils (TINs) are highly heterogeneous and mostly immunosuppressive in the tumor immune microenvironment (TIME). Current biomarkers of TINs and treatment strategies targeting TINs have not yielded optimal responses in patients across cancer types. Here, we separated human and mouse neutrophils into three developmental stages, including promyelocyte (PM), myelocyte & metamyelocyte (MC & MM), and band & segmented (BD & SC) neutrophils. Based on this separation, we observed the predominance of human but not mouse MC & MM-stage neutrophils in bone marrow (BM), which exhibit potent immunosuppressive and tumor-promoting properties. MCs & MMs also occupy the majority of TINs among patients with 17 cancer types. Moreover, through the creation of a NOD/ShiLtJGpt-Prkdc^em26Cd52Il2rg^em26Cd22/Gpt (NCG)-Gfi1^−/− human immune system (HIS) mouse model, which supports efficient reconstitution of human TIN, we found a significant increase of BM MCs & MMs in tumor-bearing mice. By comparing the single-cell RNA sequencing analysis results of human neutrophils from both BM and tumors, we found that CD63 and Galectin-3 distinguish MC & MM from neutrophil populations in cancer patients. Furthermore, we proposed a strategy with Fms-like tyrosine kinase 3 ligand to specifically induce the trans-differentiation of MCs & MMs into monocytic cells, and trigger tumor control in NCG-Gfi1^−/− HIS mice. Thus, our findings establish an essential role of human MC & MM-stage neutrophils in promoting cancer progression, and suggest their potential as targets for developing potential biomarkers and immunotherapies for cancer.

https://doi.org/10.1038/s41422-025-01145-0

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