For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and is the most important prognostic factor. Yet, LN metastases can harbor distinct tumor subclones from those within distant metastases, calling into question their role in distant metastasis. Here, we develop a syngeneic mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that a tumor-intrinsic interferon response program confers enhanced LN metastatic potential by upregulating MHC-I and PD-L1, enabling evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce regulatory T cells (Tregs), and generate tumor-specific immunosuppression that subsequently facilitates colonization of distant tissues. These effects extend to human cancers as well as additional cancers in mice, implicating a conserved mechanism by which malignancies spread to distant sites through systemic suppression of anti-tumor immunity.
