Type I interferon signaling instills divergent metastatic phenotypes and immunotherapy responses

Metastatic colonization of distant tissues is responsible for most cancer deaths, yet while this colonization is typically preceded by lymph node (LN) metastasis, the clonal and functional relationships between metastases in these tissues remain unclear. Reconstruction of metastatic phylogenies in mouse models and patients suggests that LN and distant organ metastases are often seeded by independent clones, yet no genetic alterations have bene found to account for this divergent seeding. Here, we discover opposing roles for interferon signaling in metastasis to LNs and distant organs. We uncover that exposure to leukocyte-derived type I interferon promotes LN metastasis while impairing spread to distant organs by inducing interferon-stimulated gene (ISG) expression. Further, while LN metastases have previously been demonstrated to disrupt anti-tumor immunity, we find that ISG expression induced during LN metastasis sensitizes tumors to immune checkpoint blockade (ICB). By mimicking the phenotype of LN metastases through delivery of type I interferon, ICB refractory primary tumors and distant metastases can be sensitized to ICB. Collectively, these findings demonstrate that the immune system conditions tumors for LN metastasis through type I interferon secretion while impairing distant spread and that this axis can be exploited to render immunotherapy resistant tumors sensitive to immune checkpoint blockade therapy.