Recognizing that the transformative effects of immunotherapy are currently limited to a minority of patients with cancer, research efforts are increasingly focused on expanding and enhancing clinical responses by combining immunotherapies; the repurposing of existing drugs is an attractive approach, given their well-characterized safety and pharmacokinetic profiles. Receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were initially described in the context of T cell–dendritic cell interactions; however, the discovery of an obligate role of RANK signalling in osteoclastogenesis led to the development of the anti-RANKL antibody denosumab for antiresorptive indications, including bone metastases. Randomized clinical trials and post-marketing surveillance studies have established the acceptable safety profile of denosumab. More recently, several case reports involving patients with advanced-stage melanoma have described remarkable responses following concurrent treatment with denosumab and immune-checkpoint inhibitors. Randomized trials assessing similar combinations in patients with melanoma or renal cell carcinoma are now underway. Herein, we discuss the hallmark clinical trials of denosumab in light of possible immunological effects of this agent. We highlight the role of immune cells as sources of RANK and RANKL in the tumour microenvironment and review data on RANKL inhibition in mouse models of cancer. Finally, we describe hypothetical immune-related mechanisms of action, which could be assessed in clinical trials of immune-checkpoint inhibitors and denosumab in patients with cancer.