Pan-cancer bone metastasis atlas at single-cell resolution identifies a distinct tumor-associated macrophage subset for mediating Denosumab-induced immunosensitization in lung cancer bone metastasis

Lung cancer (LC), prostate cancer (PC), and breast cancer (BC) are the three most prevalent cancers that lead to bone metastasis (BoM). In this study, we conducted an integrated analysis of single-cell transcriptomic data from the primary tumors and BoM across PC, LC, and BC. We discover a novel subtype of tumor-associated macrophages (TAMs) that are positive both for matrix metalloproteinase 19 (MMP19) and receptor activator of nuclear factor-κB (RANK) expression (MMP19⁺ RANK⁺ TAMs). MMP19⁺ RANK⁺ TAMs demonstrate an increased level of M2 polarization and act as a critical driving factor for LC-BoM. MMP19⁺ RANK⁺ TAMs are organized in a ring-like arrangement surrounding the tumor nests, constructing a barrier structure that impedes the infiltration of CD8⁺ T cells into the tumor core in LC-BoM. RANKL inhibitor Denosumab has been shown to effectively reduce the level of M2 polarization, decrease the population of MMP19⁺ RANK⁺ TAMs, and disrupt their barrier structure. Denosumab facilitates the infiltration of CD8⁺ T cells into the interior of LC-BoM tissues. Based on this mechanism, we observed in both clinical cohorts and preclinical models that RANKL inhibitor can enhance the efficacy of immunotherapy in treating LC-BoM.