Neutrophils orchestrate pre-metastatic immunosuppressive bone marrow remodeling during prostate cancer metastasis
Year: 2026
Type: preprint
Abstract: The dynamic reprogramming of the bone marrow (BM) microenvironment during metastatic progression is poorly defined. Through single-cell profiling of BM samples spanning benign conditions, high-risk bone metastatic potential localized prostate cancer (HMP) and established bone metastatic prostate cancer (PCa), we uncovered a primary tumor-to-BM signaling axis that orchestrates niche formation through neutrophil-mediated remodeling. Tumor-associated neutrophils (TANs) emerge during the HMP stage, persist throughout metastatic progression, correlate with poor patient prognosis, and exhibit direct immunosuppressive activity that contributes to a BM environment permissive to metastatic colonization. Functional and genetic studies showed that tumor-associated systemic IGF1 reprogrammed BM neutrophils through IGF1R-MAPK/ERK-KLF4 signaling, with IL-1β, reactive oxygen species and nitric oxide contributing to TAN-mediated T cell suppression. Tumor-cell Igf1 perturbation, IGF1R blockade and neutrophil-specific Igf1r deletion attenuated TAN-associated BM remodeling, and reduced subsequent bone metastatic progression. In bone-metastasis models, combined IGF1R and PD-1 blockade suppressed bone-metastatic progression. Translationally, our investigator-initiated clinical trial ( NCT06866548 ) of teprotumumab plus tislelizumab in patients with established metastatic castration-resistant prostate cancer (mCRPC) provided initial safety data and exploratory clinical observations. Together, these findings identify IGF1R-dependent neutrophil reprogramming as a functionally important component of the evolving PCa bone metastatic microenvironment and provide a rationale for therapeutic targeting of IGF1R signaling together with immune checkpoint blockade.
Institutions: Sichuan University, State Key Laboratory of Biotherapy, Second Military Medical University, Shanghai Changzheng Hospital, Wuxi Fourth People's Hospital, Jiangsu Cancer Hospital, Nanjing Medical University, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou Institute of Systems Medicine, First Affiliated Hospital Zhejiang University, Shanghai Medical College of Fudan University, Fudan University, Fudan University Shanghai Cancer Center, State Key Laboratory of Molecular Oncology, Shanghai Jiao Tong University, Shanghai First People's Hospital
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Natural Science Foundation of Shanghai, BeiGene, Innovent Biologics, Shanghai Municipal Health Commission, National Natural Science Foundation of China, Shanghai Municipal Education Commission, Shanghai Rising-Star Program, National Science and Technology Major Project, Natural Science Foundation of Sichuan Province, National Key Research and Development Program of China
OpenAlex ID: W7221070589