CHI3L3+ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases

Tao Shi; Wei Liu; Yuting Luo; Kaijie Liang; Shiji Ren; Xueru Song; Fangcen Liu; Chun Lu; Daniel Hirschhorn; Hanbing Wang; Yipeng Zhang; Yiran Cai; Yue Wang; Yunfeng Pan; Wenqi Liu; Yang Nie; Ziliang Zhang; Lixia Yu; Shuai Ding; Baorui Liu; Taha Merghoub; Yan Li; Jia Wei

doi:10.1016/j.ccell.2025.07.007

CHI3L3⁺ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases

Cancer Cell. 2025 Oct 13;43(10):1937-1957.e11. doi: 10.1016/j.ccell.2025.07.007. Epub 2025 Aug 7.

Authors

Tao Shi¹, Wei Liu², Yuting Luo³, Kaijie Liang³, Shiji Ren³, Xueru Song³, Fangcen Liu⁴, Chun Lu², Daniel Hirschhorn⁵, Hanbing Wang³, Yipeng Zhang³, Yiran Cai³, Yue Wang³, Yunfeng Pan³, Wenqi Liu³, Yang Nie³, Ziliang Zhang⁶, Lixia Yu³, Shuai Ding⁷, Baorui Liu³, Taha Merghoub⁸, Yan Li⁹, Jia Wei¹⁰

Affiliations

¹ Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
² National Resource Center for Mutant Mice and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China.
³ Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
⁴ Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
⁵ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA.
⁶ Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China.
⁷ Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
⁸ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA. Electronic address: tmerghoub@med.cornell.edu.
⁹ Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; National Resource Center for Mutant Mice and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, China; Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China; Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi, China. Electronic address: yanli@nju.edu.cn.
¹⁰ Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China; Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China; Engineering Research Center of Protein and Peptide Medicine, Nanjing University, Nanjing, China. Electronic address: jiawei99@nju.edu.cn.

PMID: 40780215
DOI: 10.1016/j.ccell.2025.07.007

Abstract

Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer, particularly in refractory tumors including bone metastases, is not well understood. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. Dickkopf1 (DKK1) induces an immature-like functional state in neutrophils, which exhibit robust immunosuppressive capabilities to inhibit anti-tumor response of CD8⁺ T cells. Mechanistically, the DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, which is necessary for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, blocking DKK1 promotes neutrophil maturation to improve the immune microenvironment, induces tumor shrinkage, and enhances ICB therapy response in multiple bone metastasis mouse models. These findings uncover a critical role for immature neutrophils in bone metastases and suggest a potential strategy for modulating neutrophils to improve cancer immunotherapy.

Keywords: CHI3L3; DKK1; bone metastases; cancer immunotherapy; immature neutrophils.

MeSH terms

Animals
Bone Neoplasms* / drug therapy
Bone Neoplasms* / immunology
Bone Neoplasms* / secondary
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Female
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Intercellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Inbred C57BL
Neutrophils* / immunology
Neutrophils* / metabolism
Signal Transduction
Tumor Microenvironment / immunology

Substances

Immune Checkpoint Inhibitors
Intercellular Signaling Peptides and Proteins