Immune checkpoint inhibition in bone metastases: lesion response heterogeneity, the osteoimmune niche, and microenvironment-directed therapy.

Abstract

Bone metastases are common in advanced solid tumors and are clinically important not only because they cause skeletal-related events, including bone pain, pathological fractures, and spinal cord compression, but also because they may influence responses to immune checkpoint inhibitors (ICIs). Clinical evidence has consistently associated bone metastases with poorer survival after ICI treatment. Although some studies suggest that the relative benefit of ICIs may be reduced in patients with bone metastases, most available evidence is retrospective and lacks adequate treatment-interaction testing. This apparent reduction in benefit therefore cannot be clearly distinguished from adverse baseline prognosis, greater disease burden, or confounding related to concomitant treatments. Lesion-level studies further suggest that bone and nonbone lesions may follow discordant response trajectories. Assessment of bone-lesion response is complicated by the limited measurability of bone-only lesions under RECIST 1.1 and by treatment-related sclerosis, bone flare, and mixed responses. Mechanistically, bone metastases may establish a site-specific osteoimmune niche in which abnormal bone remodeling, vascular and stromal reorganization, myeloid immunosuppression, and impaired T-cell infiltration and effector function jointly constrain local antitumor immunity. RANKL inhibition and bone-directed radiotherapy are clinically available and may have immunomodulatory effects, but current evidence does not establish that either approach consistently enhances the antitumor activity of ICIs beyond skeletal protection or local control. Most other microenvironment-directed strategies remain at the preclinical or early translational stage. Future studies should distinguish bone-lesion antitumor response from systemic disease control and skeletal clinical outcomes. Prespecified treatment-interaction analyses, longitudinal multimodal imaging, paired sampling of bone and nonbone lesions, and mechanism-embedded clinical trials will be required to determine whether specific osteoimmune niche states can guide patient selection and combination therapy.