Decoding the human bone metastatic niche at single-cell resolution: convergent ecosystems, therapeutic vulnerabilities, and the spatial frontier

Bone metastases arise from biologically diverse solid malignancies but develop within a shared and highly specialized skeletal microenvironment. Recent advances in single-cell transcriptomics have enabled direct characterization of human bone metastatic lesions and have shifted the field from tumor-specific descriptions toward cross-cancer ecosystem models. Emerging pan-cancer atlases reveal partial convergence across malignancies, including recurrent suppressive myeloid states, transcriptionally defined T Cell exhaustion programs, remodeled stromal and osteolineage compartments, specialized endothelial niches, and distinct malignant-cell programs observed in bone. Several of these ecosystem features nominate candidate therapeutic vulnerabilities rather than established dependencies. Combined immune-checkpoint blockade, modulation of osteoimmune macrophage states, and disruption of stromal chemokine signaling have each received different levels of support, ranging from transcriptomic or spatial association to in vitro and in vivo perturbation, while prospective clinical validation is lacking. Because recurrence across analytical studies is not equivalent to independent replication or bone specificity, we distinguish cross-cancer recurrence from bone enrichment and from mechanistically supported skeletal-niche adaptation. Current datasets also reveal substantial heterogeneity between patients, tumor types, anatomical compartments, treatment exposures, and analytical frameworks, arguing against a single universal bone metastatic niche. This mini review synthesizes the rapidly evolving human single-cell literature on established bone metastases, evaluates candidate niche-associated therapeutic vulnerabilities, and outlines the spatial and functional validation required for clinical translation.