Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination anti-RANKL and immune checkpoint blockade in anti-tumor immunity will be studied in upcoming clinical trials. RANKL-RANK interactions in the tumor microenvironment between infiltrating lymphocytes and myeloid cells may represent a novel axis of immune suppression which could be targeted with combinations of existing therapies. In this presentation, I will discuss data illustrating the combinatorial efficacy of co-targeting RANKL and CTLA4 in mouse models of subcutaneous and metastatic cancer, predominantly in melanoma. The results provide insight into potential mechanisms of anti-melanoma efficacy as described in case reports of patients receiving combination ipilimumab and denosumab in advanced melanoma, and suggest translational markers for consideration in the design of future clinical trials of similar combinations.