Neutrophils orchestrate pre-metastatic immunosuppressive bone marrow remodeling during prostate cancer metastasis
- 1Shanghai Changzheng Hospital, Naval Medical University
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-1{beta}, 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.
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BibTeX
@misc{tang2026neutrophils,
title = {{Neutrophils orchestrate pre-metastatic immunosuppressive bone marrow remodeling during prostate cancer metastasis}},
author = {Y. Tang and X. Zhou and D. Li and Y. Liu and G. Zhu and J. Wang and X. Wu and D. Zhong and Z. Li and H. Huang and B.-Z. Qian and Y. Zhang and J. Xiao and Z. Yue and S. Chen and S. Ren},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757800},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757800v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Neutrophils orchestrate pre-metastatic immunosuppressive bone marrow remodeling during prostate cancer metastasis
AU - Y. Tang
AU - X. Zhou
AU - D. Li
AU - Y. Liu
AU - G. Zhu
AU - J. Wang
AU - X. Wu
AU - D. Zhong
AU - Z. Li
AU - H. Huang
AU - B.-Z. Qian
AU - Y. Zhang
AU - J. Xiao
AU - Z. Yue
AU - S. Chen
AU - S. Ren
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757800
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757800v1
AB - 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-1{beta}, 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.
ER -