Exploring immunotherapy resistance in bone metastasis: mechanisms and optimization of combined treatment strategies-a narrative review.
- 1Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, China.
- 2Department of Nuclear Medicine, PLA 960th Hospital, Jinan, China.
Abstract
Bone metastasis is a common complication of advanced solid tumors and has been associated with poor efficacy of immune checkpoint inhibitors (ICIs). This review aims to summarize the clinical evidence linking bone metastasis to reduced ICI efficacy, to dissect the bone marrow microenvironment (BMM)-mediated mechanisms of immunotherapy resistance, and to evaluate current and emerging combination strategies. We searched PubMed, Embase, and Web of Science from database inception to August 2026 for studies on bone metastasis, immunotherapy, immune resistance, and combination therapy. Clinical evidence was graded from randomized controlled trials (RCTs) (level I) to preclinical (animal or in vitro) studies (level V). Clinical studies consistently show lower response rates and shorter survival in patients with bone metastasis treated with ICIs, although most data are retrospective and unadjusted. Mechanistically, tumor cells exploit the immune-privileged hematopoietic stem cell (HSC) niche, hypoxia-driven metabolic reprogramming, immunosuppressive immune cell remodeling, and bone-immune crosstalk to evade immune attack. Combination strategies, including bone-targeted agents, radiotherapy, and anti-angiogenic therapy, show promise but are supported mainly by retrospective evidence; emerging approaches [nanomaterials, the sialic acid-Siglec axis, transforming growth factor-β (TGF-β) inhibition, and gut microbiota modulation] remain preclinical. Bone metastasis represents an organ-specific model of immunotherapy resistance. Mechanism-based combination strategies and bone-specific biomarkers are promising avenues to improve ICI efficacy, but high-level prospective evidence is urgently needed.
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BibTeX
@article{zhu2026exploring,
title = {{Exploring immunotherapy resistance in bone metastasis: mechanisms and optimization of combined treatment strategies-a narrative review.}},
author = {Junquan Zhu and Min Li},
journal = {Translational cancer research},
year = {2026},
month = sep,
doi = {10.21037/tcr-2026-1860},
url = {https://europepmc.org/article/MED/42997882},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Exploring immunotherapy resistance in bone metastasis: mechanisms and optimization of combined treatment strategies-a narrative review.
AU - Junquan Zhu
AU - Min Li
PY - 2026
DA - 2026/09/28
JO - Translational cancer research
DO - 10.21037/tcr-2026-1860
UR - https://europepmc.org/article/MED/42997882
AB - Bone metastasis is a common complication of advanced solid tumors and has been associated with poor efficacy of immune checkpoint inhibitors (ICIs). This review aims to summarize the clinical evidence linking bone metastasis to reduced ICI efficacy, to dissect the bone marrow microenvironment (BMM)-mediated mechanisms of immunotherapy resistance, and to evaluate current and emerging combination strategies. We searched PubMed, Embase, and Web of Science from database inception to August 2026 for studies on bone metastasis, immunotherapy, immune resistance, and combination therapy. Clinical evidence was graded from randomized controlled trials (RCTs) (level I) to preclinical (animal or in vitro) studies (level V). Clinical studies consistently show lower response rates and shorter survival in patients with bone metastasis treated with ICIs, although most data are retrospective and unadjusted. Mechanistically, tumor cells exploit the immune-privileged hematopoietic stem cell (HSC) niche, hypoxia-driven metabolic reprogramming, immunosuppressive immune cell remodeling, and bone-immune crosstalk to evade immune attack. Combination strategies, including bone-targeted agents, radiotherapy, and anti-angiogenic therapy, show promise but are supported mainly by retrospective evidence; emerging approaches [nanomaterials, the sialic acid-Siglec axis, transforming growth factor-β (TGF-β) inhibition, and gut microbiota modulation] remain preclinical. Bone metastasis represents an organ-specific model of immunotherapy resistance. Mechanism-based combination strategies and bone-specific biomarkers are promising avenues to improve ICI efficacy, but high-level prospective evidence is urgently needed.
SN - 2218-676X
SN - 2219-6803
ER -