IFNγ Prevents Outgrowth of Metastasis-Promoting Lymphatic Vessels

Lymphatic vessels play complex roles in tumor biology, as intratumoral and peritumoral vessels can potentially restrain tumor growth by facilitating immune surveillance but simultaneously promote metastasis to associated lymph nodes. Given that distinct lymphatic phenotypes may underlie the dichotomous effects of tumor-associated lymphatic vasculature, Karakousi and colleagues assessed the association between the formation of lymphatic vessels, termed lymphangiogenesis, and the degree of antitumor immune surveillance in multiple murine models of melanoma and lung adenocarcinoma. In each model, intratumoral lymphangiogenesis was inversely correlated with cytotoxic immunity, and these observations were validated in data from patients with melanoma treated with immune checkpoint inhibitors. In an immunogenic model of melanoma characterized by high levels of CD8+ T cell–derived IFNγ, the lymphatic-specific loss of IFNγ sensitivity, through Ifngr1 deletion within the lymphatic endothelium, was sufficient to trigger intratumoral lymphangiogenesis, suggesting that IFNγ directly acts on lymphatic endothelial cells to restrain intratumoral lymphatic proliferation. Single-cell RNA sequencing analyses of endothelial cells from tumor-bearing mice with or without Ifngr1 deletion revealed that IFNγ signaling regulated transcriptional trajectories in lymphatic endothelial cells. Specifically, IFNγ maintained a mature, quiescent transcriptional program and blocked the developmental trajectory that otherwise would lead to an immature transcriptional program resembling the expression of cells found at the tips of lymphatic vessels. By limiting intratumoral lymphatic endothelial cell proliferation and by restraining the expansion of an immature, tip-like state, IFNγ ultimately restrained lymph node metastasis. Mechanistically, IFNγ signaling inhibited oxidative phosphorylation and mitochondrial reactive oxygen species, which were required for intratumoral lymphangiogenesis. Lymphatic-specific deletion of a subunit of complex III of the electron transport chain markedly depleted intratumoral vasculature and decreased the immature, tip-like, pro-metastatic program. Further in vivo investigation provided evidence for a model in which, while peritumoral lymph vessels support immune cell migration and antitumor immune surveillance, intratumoral lymphatic vasculature depends on mitochondrial respiration for the expansion of an immature lymphatic state that promotes metastasis. Together, these findings shed light on the diverse roles of intratumoral and peritumoral lymph vessels and suggest the therapeutic potential of specifically targeting the metabolic requirements of intratumoral lymphatics.Karakousi T, Cristaldi V, Lopes de Oliveira ML, Delclaux I, Besson NR, Geraldo LH, et al. IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma. Cancer Cell 2026 Jan 22 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.