On initial diagnosis of primary breast cancer, a large proportion of patients already have tumour cells that have disseminated away from the breast and are in the circulation or lodged in distant tissues such as the bone marrow. For this reason, it is imperative to know what controls tumour cell fate after dissemination and the molecular mechanisms driving tumour cell outgrowth into clinically detectable metastases. Our recent data suggest that a key step in tumour cell survival and outgrowth in bone is immune escape. Using the syngeneic 4T1.2 model of spontaneous mammary metastasis to bone we discovered that primary breast tumour cells express an innate immune pathway that is regulated by interferon regulatory factor 7 (Irf7), and that upon spread to the bone there is a dramatic decrease in the expression of this pathway. Restoration of tumour cell Irf7 signalling suppressed metastasis to bone and prolonged metastasis-free survival and this was dependent on NK and CD8+ T cell responses. Additionally, loss of the type I IFN receptor in the host stroma (Ifnar1-/- Balb/c mice) blocked Irf7-driven metastasis suppression, suggesting that cross-talk between tumour cells and the immune system (by secretion of type I IFN) dictates metastasis in breast cancer. In further support of this, in various non-bone metastatic breast cancer models we observed the development of bone metastases using Ifnar1-/- mice. These findings have clinical relevance as decreased primary tumour expression of the type I IFN signature predicted an increased risk of bone metastatic relapse in breast cancer patients. Our work is now focused on identifying the immune responses that are stimulated by tumour cell interferon secretion and are critical for site-specific metastasis suppression.