Despite improved detection and treatment of early-stage breast cancer, metastatic disease remains a clinical challenge as conventional and immune-based therapies offer little long-term survival benefit. About 75% of breast cancer metastases occur in bone, which can be treatment resistant and associated with severe morbidity and high mortality rates. The biological changes promoting outgrowth of disseminated cancer cells in bone are not fully understood, but one mechanism is microenvironment-induced immune suppression that renders bone metastases unresponsive to anti-tumour immunity. Our laboratory has previously identified a critical pathway associated with bone metastatic outgrowth and reduced cellular immunogenicity: suppression of tumour-intrinsic type I interferon (IFN) signalling, including hundreds of interferon-regulated genes crucial for innate and adaptive immune response and anti-tumour immunity. Thus, targeted approaches to restore IFN signalling in metastatic cells could have important therapeutic implications. This project used genome-wide CRISPR/Cas9 screening in bone metastatic lines in vitro to identify novel targets to restore IFN signalling. We transduced bone metastatic cells isolated from the 4T1.2 and EO771.LMB mouse models of breast cancer with an interferon-stimulated response element (ISRE) GFP/Luc2 reporter system, which revealed significant reductions in ISRE activity both at baseline and with TLR-agonist stimulation compared to primary tumour lines. After Cas9 transduction, we performed a CRISPR/Cas9 knockout screen, and isolated GFP positive cells (indicating enhanced ISRE activity) via flow cytometry. This screen identified >100 genes that, when suppressed, restore type I IFN signalling, including confirmed targets relevant to the cGAS/STING signalling pathway. These key hits are being validated for their ability to alter IFN signalling and cellular immunogenicity in in vitro and will be further validated for their effectiveness alongside traditional therapies in vivo. Identified through ISRE reporter and CRISPR/Cas9 screening, these gene targets offer novel therapeutic strategies for combatting late-stage breast cancer, enhancing IFN signalling in bone metastasis and increasing cancer vulnerability to immune-based therapeutics.