RT Journal Article
SR Electronic
T1 Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis
JF Cancer Biology & Medicine
JO Cancer Biology & Medicine
FD China Anti-Cancer Association
SP 20260168
DO 10.20892/j.issn.2095-3941.2026.0168
A1 Luo, Yuting
A1 Cai, Yiran
A1 Jiang, Zizheng
A1 Zheng, Ke
A1 Ren, Shiji
A1 Yu, Lixia
A1 Liu, Baorui
A1 Shi, Tao
A1 Wei, Jia
YR 2026
UL http://www.cancerbiomed.org/content/early/2026/07/27/j.issn.2095-3941.2026.0168.abstract
AB 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: The composition and phenotypic characteristics of myeloid cells in the bone TME were analyzed. Mechanistic studies were conducted using ex vivo co-culture systems and an in vivo Ckap4fl/flS100a8Cre (neutrophil-specific Ckap4 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: The findings herein showed the DKK1-CKAP4 axis to be a key regulator of myeloid-driven immunosuppression in the bone TME. The combination of DKK1 blockade with zoledronic acid represents a potential therapeutic strategy for bone metastases.The data generated in this study are available upon request from the corresponding author.