The presence of bone metastatic lesions is considered a lethal and frequent complication in breast cancer patients, with over 50% of all first distant relapses occurring in the skeleton. To date, conventional therapies are largely palliative rather than curative, once progression to bone has occurred, and immunotherapeutics, successful in other solid malignancies, have yielded little long-term benefit in the bone-metastatic setting. The failure of immune-targeted agents has been linked to the unique immunosuppressive microenvironment of the bone, and several immnunoevasive mechanisms that hinder therapeutic effectiveness. Type I interferons (IFNs) are secreted cytokines that exert potent anti-tumour activity and play a key role in dictating tumour cell immunogenicity, immune activation and immunotherapeutic efficacy in the tumour microenvironment. Our laboratory has identified the loss of tumour-intrinsic type I IFN) signalling in breast cancer as a critical driver of immune evasion in the bone-metastatic niche. As such, the restoration of type I IFN signalling in breast cancer cells has been regarded as a potential strategy to improve tumour cell visibility and promote the elimination of breast cancer cells in bone. The current project aims to identify novel IFN-activating compounds in breast cancer models. Using high-throughput screening (HTS) technology, we have screened an unbiased compound library against stably transfected murine and human cell lines expressing a type I IFN reporter system. Our identified hits include chromatin-modifying compounds, suggesting an epigenetic contribution to IFN loss and reduced immunogenicity of bone-metastatic cells. Using syngeneic breast cancer models, we further assessed the activity of select hits to restore immunogenicity in bone metastases-derived cells. Our preliminary data suggests new therapeutic avenues for targeting bone-metastatic breast cancer to reduce patient mortality.