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

Cell Research volume 35, pages 588–606 (2025)Cite this article

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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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Fig. 1: Characterization of human BM neutrophils.
Fig. 2: MC & MM-stage neutrophils in human BM are long-lived and tumor-promoting.
Fig. 3: MC & MM neutrophils constitute the majority of TINs across tumor types.
Fig. 4: The proportion of MC & MM neutrophils is increased in the BM of cancer patients and tumor-bearing NCG-Gfi1−/− HIS mice.
Fig. 5: CD63 and Galectin-3 distinguish MC & MM from neutrophil populations in cancer patients.
Fig. 6: Flt3L transdifferentiates MC & MM-stage neutrophils into monocytic cells.
Fig. 7: Flt3L trans-differentiation treatment controls tumor growth in NCG-Gfi1−/− HIS model.
Fig. 8: A schematic diagram illustrating dynamics of human MC & MM-stage neutrophils across physiological and tumor conditions.

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Data availability

This study did not generate new materials. The scRNA-seq and bulk RNA-seq data have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences that are publicly accessible at https://ngdc.cncb.ac.cn/gsa (GSA: HRA011772, under GSA for Human category). Original code has been deposited at GitHub and is available at https://github.com/yuzu1999/Neutrophils.

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Acknowledgements

This work was funded by grants from the National Science and Technology Major Program (2023ZD0500400), the Fundamental Research Funds for the Central Universities (2024300408, XJ2024003602), the National Natural Science Foundation of China (32471000, U24A20378, 82373263, 82403835), the National Key R&D Program of China (2023YFC2506400), the Jiangsu Provincial Science and Technology Plan Special Fund (BK20232018) and the Funding of the Major Program of Shenzhen Bay Laboratory.

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Author notes

  1. These authors contributed equally: Wei Liu, Tao Shi.

Authors and 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

    Wei Liu, Chun Lu, Zijian Zhang, Shuang Liu, Haiqiao Sun & Yan Li

  2. Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China

    Tao Shi, Keying Che, Yuting Luo, Hanbing Wang & Jia Wei

  3. Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA

    Tao Shi, Daniel Hirschhorn & Taha Merghoub

  4. Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA

    Daniel Hirschhorn & Taha Merghoub

  5. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Shaorui Liu, Yan Wang & Heping Xu

  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

    Jun Lu, Yuan Liu & Dongquan Shi

  7. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China

    Shuai Ding

  8. Laboratory of Genetic Regulators in the Immune System School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China

    Liaoxun Lu

  9. GemPharmatech Co., Ltd., Jiangbei New Area, Nanjing, Jiangsu, China

    Jianming Xu & Jun Xin

  10. Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China

    Yinming Liang

  11. Center of Disease Model and Immunology, Hunan Academy of Chinese Medicine, Changsha, Hunan, China

    Yinming Liang

  12. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China

    Jia Wei

  13. Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, Jiangsu, China

    Jia Wei

  14. Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Jia Wei

  15. Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing, Jiangsu, China

    Yan Li

  16. Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi, Jiangsu, China

    Yan Li

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  1. Wei Liu
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Contributions

Y. Li and W.L. designed the study. Y. Li, J.W., T.M. and Y. Liang supervised the study and revised the manuscript. W.L. performed the experiments and analyzed the data. with the assistance from T.S., C.L., K.C., Z.Z., Y. Luo, D.H., H.W., Shaorui L., Y.W., Shuang L., H.S., J.L., Y. Liu, D.S., S.D., H.X., L.L., J.X. and Jun X. T.S. and W.L. drafted the manuscript. The clinical samples were provided by S.D., Y. Luo and Y. Liu. The bioinformatic analyses were conducted by C.L. NCG-Gfi1−/− mice were generated by Y. Li, W.L., L.L., J.X., Jun X. and Y. Liang. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Yinming Liang, Taha Merghoub, Jia Wei or Yan Li.

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Competing interests

Y. Li is currently consulting for GemPharmatech Co. J.W. has received research funding from Leap Therapeutics. T.M. is a consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTx, Normunity and Pfizer. T.M. is a cofounder and equity holder of IMVAQ Therapeutics. T.M. has received research funding from Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics, and currently receives research funding from Bristol-Myers Squibb, Enterome SA, and Realta Life Sciences. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. The rest of authors declare no competing interests.

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Liu, W., Shi, T., Lu, C. et al. Human myelocyte and metamyelocyte-stage neutrophils suppress tumor immunity and promote cancer progression. Cell Res 35, 588–606 (2025). https://doi.org/10.1038/s41422-025-01145-0

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