The spread of tumour cells to bone is a frequent and fatal complication of breast cancer, with over 50% of all first distant relapses occurring in the skeleton. To date, conventional therapies largely confer palliative rather than curative care in 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 immune evasive mechanisms that dampen tumour cell visibility and hinder therapeutic effectiveness. Type I IFNs are secreted cytokines that have potent antitumour activities and play a key role in dictating tumour cell immunogenicity, immune activation and immunotherapeutic efficacy in the tumour microenvironment. Our laboratory has identified that the loss of tumour-intrinsic type I interferon (IFN) signalling in breast cancer cells in bone facilitates tumour outgrowth and is a critical driver of immune evasion in the 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 cells. Using high-throughput screening (HTS) technology linked to a unique type I IFN reporter system, we have screened an unbiased compound library to reveal agents that stimulate and/or restore IFN signalling in metastatic mouse and human cell lines. We have identified hits that include chromatin-modifying compounds, suggesting an epigenetic component of IFN signalling suppression in breast cancer cells. Using syngeneic breast cancer models, we further assessed the activity of a selected hit to restore immunogenicity in bone metastases-derived cell lines. Our preliminary data suggests new science-guided approaches for enhancing immunotherapeutic response against metastatic disease and reducing patient mortality.