Breaking the immune “cold niche” in bone metastasis: core mechanisms of the multidimensional interwoven regulatory network and precision breakthrough strategies

Bone metastasis is a pivotal hallmark of advanced malignant tumors. It severely impairs the therapeutic efficacy of immune checkpoint inhibitors (ICIs) and serves as an independent risk factor for poor prognosis of immunotherapy in solid tumors. Most existing reviews are confined to traditional research frameworks and have not yet resolved this clinical dilemma. This paper systematically elaborates on the core mechanisms underlying the poor efficacy of immunotherapy for bone metastasis. It clarifies that the immune suppression mediated by the bone metastatic microenvironment (BME) is not induced by a single factor, but rather a consequence of the cross-regulation of immunity, metabolism, bone matrix, blood vessels, epigenetics, microbiota, and nerves. From seven dimensions—immune cell-mediated immune escape, bone matrix-immune cell crosstalk, vascular-mediated immune suppression, metabolic-immune cross-regulation, epigenetic disorders, microbiota-osteoimmune axis imbalance, and neuro-immune-bone metastasis regulation—the study comprehensively sorts out the key nodes of immunotherapy resistance and clarifies the core cellular, molecular, and microenvironmental interaction mechanisms of this cross-regulatory network. On this basis, this paper explores a multi-target combined therapeutic strategy of “breaking the vicious cycle by targeting key nodes, restoring anti-tumor immunity with ICIs, and realizing local-systemic synergism”, including combined bone matrix-immune targeted therapy, immune phenotype-based precise treatment, local-systemic synergistic immunotherapy and multi-dimensional microenvironment remodeling regimens.Finally, the paper prospects future research directions, including in-depth mechanism analysis, new target development, precision diagnosis and treatment innovation, and clinical translation. It aims to systematically summarize current mechanisms and provide theoretical reference and novel insights for developing precise immunotherapeutic strategies against bone metastasis. 1. Bone metastasis severely impairs the efficacy of immune checkpoint inhibitors (ICIs) across multiple cancer types (e.g., NSCLC, RCC, urothelial carcinoma), characterized by reduced objective response rate (ORR), shortened progression-free survival (PFS) and overall survival (OS), and constitutes an independent poor prognostic factor for cancer immunotherapy. 2. The poor efficacy of immunotherapy in bone metastasis stems from a multidimensional cross-regulatory network involving immunity, metabolism, bone matrix, blood vessels, epigenetics, microbiota and nerves, which forms a vicious cycle of “immune suppression-bone matrix destruction-metabolic disorder-vascular abnormality”. 3. A potential multi-target combined therapeutic framework of “targeting key nodes to break the vicious cycle + ICIs to restart anti-tumor immunity + local-systemic synergy” is summarized and prospected, covering bone matrix-immune targeted combination, local-systemic synergistic immunotherapy, multidimensional microenvironment remodeling, cell therapy and neuro-immune axis targeting.