Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis

作者：Yi Luo, Yiran Cai, Zizheng Jiang, Ke Zheng, Shiji Ren, Lixia Yu, Baorui Liu, Tao Shi, Jia Wei · 发表于：Cancer Biology and Medicine · 年份：2026 · DOI：10.20892/j.issn.2095-3941.2026.0168 · 研究领域：Immune cells in cancer、Cancer Cells and Metastasis、Bone Metabolism and Diseases

OBJECTIVE: Bone metastases are refractory to current therapies, primarily owing to the immunosuppressive metastasis tumor microenvironment (TME), which is dominated by myeloid cells. However, the function and regulatory mechanisms of myeloid compartments within the bone TME are incompletely understood. Herein we sought to delineate the role of the DKK1-CKAP4 axis in shaping myeloid cell-mediated immunosuppression in bone metastases and to identify potential therapeutic strategies targeting this pathway. METHODS: knockout) mouse model to delineate the role of the DKK1-CKAP4 axis in regulating neutrophil maturation, osteoclast-like cell differentiation, and macrophage polarization. The therapeutic efficacy of DKK1 blockade in combination with zoledronic acid, as well as the impact on remodeling the TME, was further validated in bone metastasis mouse models. RESULTS: Significant expansion and predominance of myeloid cells within the bone TME was noted. Mechanistically, the DKK1-CKAP4 axis regulated the development and function of multiple myeloid populations. The DKK1-CKAP4 axis drove neutrophils toward an immature-like, immunosuppressive phenotype, promoted osteoclast-like cell differentiation, and induced macrophage polarization into an M2-like phenotype. Importantly, combined therapy with DKK1 blockade and zoledronic acid reprogrammed immunosuppressive myeloid cells, restored antitumor immunity, and significantly reduced tumor burden in bone metastasis models. CONCLUSIONS: Th...