A Pan‐Cancer Single‐Cell Atlas of Bone Metastases Reveals Convergent Malignant Programs and Coordinated Immune Dysfunction

ABSTRACT Bone metastases (BoMs) are a major clinical challenge across cancer types, yet mechanistic insights remain limited by small cohorts and insufficient profiling depth. Here, we present a single‐cell RNA sequencing atlas of 95 BoMs, 22 healthy bone marrows (hBMs) and 129 primary tumors (PTs) spanning 10 cancer types, comprising 895,475 high‐quality transcriptomes, to map cellular remodeling during bone metastatic colonization. Malignant cells in BoMs converged on chromosomal instability—high proliferative states with enhanced angiogenic programs and suppressed immune‐inflammatory and metabolic pathways. The BoM immune landscape featured reduced cytotoxic lymphoid populations and expanded exhausted T‐cell states, with pronounced cancer type‐specific heterogeneity. BoM‐resident myeloid cells showed marked suppression of antigen presentation and phagocytosis, indicating immunosuppressive reprogramming. Stromal remodeling was characterized by enrichment of immunosuppressive CAFs, depletion of antigen‐presenting fibroblasts, reduced mesenchymal MHC expression, and expanded angiogenic endothelial programs. Cell–cell communication analyses predicted strengthened CXCL12–CXCR4 stromal–immune signaling. In vitro, the CXCL12–CXCR4 axis recruited CD8 + T cells and enhanced their adhesion, spatially sequestering them from the tumor parenchyma, while CXCR4 blockade or CXCL12 knockdown significantly reduced tumor‐cell migration and invasion in vitro. This atlas defines convergent hallmarks of bone metastasis and highlights shared stromal–immune dependencies as therapeutic vulnerabilities.