Denosumab Plus Immune Checkpoint Inhibitors in Bone Metastases From Solid Tumors

Bone metastases are a common and devastating complication of advanced solid tumors, significantly impairing patients' quality of life and prognosis. Immune checkpoint inhibitor (ICI) plus bone-targeted therapies have emerged as a promising strategy to improve outcomes in patients with bone metastases. Denosumab, a fully human mAb targeting RANKL, can inhibit osteoclast-mediated bone resorption and prevent skeletal-related events. Beyond its direct bone remodeling activity, denosumab can also modulate the immune microenvironment, enhance anti-tumor immunity by reducing the release of immunosuppressive factors into the bone milieu, and improve vascular integrity within previously damaged bone tissue to facilitate immune cell infiltration into the metastatic niches. ICIs restore T-cell activity by overcoming tumor-induced immune suppression, thereby enabling more effective anti-tumor responses. Emerging evidence have suggested a potential synergy of denosumab plus ICIs, mechanistically by reinvigorating T-cell function and promoting maturation and antigen-presenting capacity of dendritic cells to further amplify adaptive immune response against metastatic bone tumors. The present narrative review summarizes the preclinical and clinical findings on this combination and discusses potential biomarkers and current challenges for the optimization of patient selection and therapeutic paradigm. Besides, we briefly overview current ongoing studies that investigate the potential antitumor synergy with denosumab plus ICIs in bone metastases.