2. Academic Validation
  3. Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression

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

  • Cell Res. 2025 Aug;35(8):588-606. doi: 10.1038/s41422-025-01145-0.
Wei Liu # 1,  Tao Shi # 2 3,  Chun Lu 1,  Keying Che 2,  Zijian Zhang 1,  Yuting Luo 2,  Daniel Hirschhorn 3 4,  Hanbing Wang 2,  Shaorui Liu 5,  Yan Wang 5,  Shuang Liu 1,  Haiqiao Sun 1,  Jun Lu 6,  Yuan Liu 6,  Dongquan Shi 6,  Shuai Ding 7,  Heping Xu 5,  Liaoxun Lu 8,  Jianming Xu 9,  Jun Xin 9,  Yinming Liang 10 11,  Taha Merghoub 12 13,  Jia Wei 14 15 16 17,  Yan Li 18 19 20
Affiliations

Affiliations

  • 1 National 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.
  • 2 Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 3 Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • 4 Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA.
  • 5 Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 6 State 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.
  • 7 Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
  • 8 Laboratory of Genetic Regulators in the Immune System School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China.
  • 9 GemPharmatech Co., Ltd., Jiangbei New Area, Nanjing, Jiangsu, China.
  • 10 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China. yinming.liang@gris.org.cn.
  • 11 Center of Disease Model and Immunology, Hunan Academy of Chinese Medicine, Changsha, Hunan, China. yinming.liang@gris.org.cn.
  • 12 Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
  • 13 Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
  • 14 Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. jiawei99@nju.edu.cn.
  • 15 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China. jiawei99@nju.edu.cn.
  • 16 Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, Jiangsu, China. jiawei99@nju.edu.cn.
  • 17 Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. jiawei99@nju.edu.cn.
  • 18 National 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. yanli@nju.edu.cn.
  • 19 Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing, Jiangsu, China. yanli@nju.edu.cn.
  • 20 Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi, Jiangsu, China. yanli@nju.edu.cn.
  • # Contributed equally.
PMID: 40664963 DOI: 10.1038/s41422-025-01145-0
Abstract

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-Prkdcem26Cd52Il2rgem26Cd22/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.

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