IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma

Summary Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNγ as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of the Ifngr1 in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNγ inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNγ induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis.