Exploring immunotherapy resistance in bone metastasis: mechanisms and optimization of combined treatment strategies—a narrative review
Year: 2026
Type: review
Abstract: Background and Objective: 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. Methods: ) studies (level V). Key Content and Findings: 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. Conclusions: 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.
Source: Translational Cancer Research
Authors: Junquan Zhu, Min Li
Institution: Shandong First Medical University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7221749187