Bone Metastasis and the Immunosuppressive Tumor Microenvironment: Mechanisms and Therapeutic Strategies
4 affiliations
- 1Affiliated School of Pediatrics, Nanjing Medical University, Nanjing, China
- 2Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
- 3Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
- 4College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Abstract
Numerous solid tumours have bone as one of their most common sites of distant metastasis, and bone metastasis causes skeletal-related events (SREs) that impair quality of life and portend poor prognosis. Bone metastasis arises not from invasive tumour cells alone but through mutual adaptation and co-evolution between tumour cells and the bone microenvironment. A key mechanism of immune evasion is the establishment of an immunosuppressive microenvironment, wherein tumour-derived cytokines, metabolic reprogramming, and extracellular vesicles drive M2 macrophage polarization, CD8+ T-cell exhaustion, regulatory T-cell enrichment, and natural killer cell dysfunction. Transforming growth factor-β (TGF-β) released during the “tumour-bone” vicious cycle further amplifies local immunosuppression, and metabolic reprogramming depletes glucose and amino acids while accumulating lactate, directly impairing effector T-cell function. Immune checkpoint inhibitor (ICI) therapy shows limited efficacy in bone metastases; however, combination strategies including bone-protective agents (denosumab, bisphosphonates), metabolic modulators, cytokine- or extracellular vesicle-targeted agents, novel nanodelivery systems, and engineered cell therapies demonstrate encouraging preclinical and early clinical promise for reversing immunosuppression. Translation still faces major challenges, including microenvironmental heterogeneity, a lack of bone-specific biomarkers, combination-related toxicity, and delivery bottlenecks. This review aims to synthesize the mechanisms underlying the immunosuppressive bone-metastasis microenvironment and to appraise current and emerging combination strategies, thereby informing individualized treatment for patients with bone metastases.
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BibTeX
@article{ba2026bone,
title = {{Bone Metastasis and the Immunosuppressive Tumor Microenvironment: Mechanisms and Therapeutic Strategies}},
author = {Minghao Ba and Yuzhu Chen and Peng Jiang and Shanshan Cai and Xin Huang and Tongmei Zhang},
journal = {Oncology Research},
year = {2026},
month = oct,
doi = {10.32604/or.2026.090531},
url = {https://doi.org/10.32604/or.2026.090531},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Bone Metastasis and the Immunosuppressive Tumor Microenvironment: Mechanisms and Therapeutic Strategies
AU - Minghao Ba
AU - Yuzhu Chen
AU - Peng Jiang
AU - Shanshan Cai
AU - Xin Huang
AU - Tongmei Zhang
PY - 2026
DA - 2026/10/28
JO - Oncology Research
DO - 10.32604/or.2026.090531
UR - https://doi.org/10.32604/or.2026.090531
AB - Numerous solid tumours have bone as one of their most common sites of distant metastasis, and bone metastasis causes skeletal-related events (SREs) that impair quality of life and portend poor prognosis. Bone metastasis arises not from invasive tumour cells alone but through mutual adaptation and co-evolution between tumour cells and the bone microenvironment. A key mechanism of immune evasion is the establishment of an immunosuppressive microenvironment, wherein tumour-derived cytokines, metabolic reprogramming, and extracellular vesicles drive M2 macrophage polarization, CD8+ T-cell exhaustion, regulatory T-cell enrichment, and natural killer cell dysfunction. Transforming growth factor-β (TGF-β) released during the “tumour-bone” vicious cycle further amplifies local immunosuppression, and metabolic reprogramming depletes glucose and amino acids while accumulating lactate, directly impairing effector T-cell function. Immune checkpoint inhibitor (ICI) therapy shows limited efficacy in bone metastases; however, combination strategies including bone-protective agents (denosumab, bisphosphonates), metabolic modulators, cytokine- or extracellular vesicle-targeted agents, novel nanodelivery systems, and engineered cell therapies demonstrate encouraging preclinical and early clinical promise for reversing immunosuppression. Translation still faces major challenges, including microenvironmental heterogeneity, a lack of bone-specific biomarkers, combination-related toxicity, and delivery bottlenecks. This review aims to synthesize the mechanisms underlying the immunosuppressive bone-metastasis microenvironment and to appraise current and emerging combination strategies, thereby informing individualized treatment for patients with bone metastases.
SN - 0965-0407
SN - 1555-3906
ER -