Immunotherapy has gained recent momentum as a viable option to effectively treat a broad subset of cancers. However, therapies such as those targeting the checkpoint protein PD-1 have shown underwhelming responses in metastatic breast and prostate cancers. This is likely linked to insufficient immune reactivity to these cancers that have a low mutational load. We have demonstrated that tumour inherent type I interferon (IFN) status is closely linked to this immune reactivity and dictates metastatic progression1. In fact, we have demonstrated that loss of key IFN regulators (IRFs) in tumour cells is strongly associated with the risk of metastatic outgrowth in bone and other tissues2. Using preclinical breast and prostate cancer models, we reveal that therapeutic restoration of systemic IFN signalling in IRF-low tumour bearing mice serves as a potent anti-metastatic, especially when administered before primary tumour resection. Additionally, we reveal that stimulating an IFN response leads to enhanced expression of PD-L1 and that combining poly I:C with anti-PD1 leads to a sustained anti-tumour T cell activation and anti-metastatic response. Our study suggests that future combination immunotherapy trials may hold most promise for targeting minimal residual disease and that such strategies may not work in patients with advanced metastases.