Despite high 5-year survival rates, breast and prostate cancer remain the second leading cause of cancer-related deaths in Australia due to metastatic recurrence. Upon diagnosis of metastatic disease, the 5-year survival rate drops to less than 30%, emphasising the critical need for strategies to target metastases. Bone is the most frequent site of spread, with bone metastases detected in over 70% of metastatic breast and prostate cancer patients, who suffer debilitating pain and fail to respond long-term to therapy, including radiotherapy and immunotherapy. Previous work from our laboratory has revealed that cancer cell arrival and growth in bone is accompanied by a loss of tumour cell-inherent type I interferon (IFN) immune signalling that renders bone metastases poorly immunogenic and resistant to immune-based therapies. Profiling of metastatic tissues from the CASCADE rapid autopsy project has confirmed the poorly immunogenic status of metastases, particularly those in bone. Based on the molecular alterations that lead to this loss of cellular immunogenicity, we have now discovered novel IFN suppressor proteins that regulate tumour immunogenicity and are promising prognostic biomarkers to predict risk of bone metastasis. Additionally, using tumour cells derived from bone, coupled to a high throughput compound screen, we have discovered new approaches to reverse type I IFN loss via epigenetic reprogramming to restore antigen presentation and enhance immune dependent, long-term metastasis-free survival. Validation of these approaches in preclinical models will lead to the design of new immunotherapy and radiotherapy combination strategies to provide an effective therapeutic option for patients with metastatic disease, improving survival outcomes.