This research identifies IFNγ as a critical regulator that prevents the spread of melanoma by altering the metabolism of lymphatic vessels. The study demonstrates that while intratumoral lymphangiogenesis typically facilitates metastasis, high levels of IFNγ from active immune cells force these vessels into a mature, stagnant state. This process occurs because IFNγ suppresses mitochondrial respiration and oxidative phosphorylation within lymphatic cells, effectively starving the energy source required for their growth. By inhibiting this metabolic reprogramming, the immune system restricts an immature, tip-like lymphatic state that would otherwise help cancer cells migrate to lymph nodes. These findings suggest that targeting lymphatic metabolism could improve immune checkpoint blockade therapy by simultaneously blocking cancer dissemination and enhancing local immune surveillance.

References:

• Karakousi T, Cristaldi V, Lopes de Oliveira ML, Medeiros Geraldo LH, González-Robles TJ, da Silva G, Breazeale AP, Encarnacion-Rosado J, Pozniak J, Kimmelman AC, Ruggles KV, Chris Marine J, Chandel NS, Lund AW. IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma. bioRxiv [Preprint]. 2024 Dec 5:2024.12.02.626426. doi: 10.1101/2024.12.02.626426. Update in: Cancer Cell. 2026 Jan 22:S1535-6108(25)00553-7. doi: 10.1016/j.ccell.2025.12.019. PMID: 39677662; PMCID: PMC11642899.