biostudies-literatureGurung SHarry J Lloyd Charitable TrustCancer Research UKManchester Biomedical Research CentreBreast Cancer NowCancer Research UK Manchester CentreNIHR Imperial Biomedical Research CentreUK Research and InnovationInstitute of Cancer ResearchRosetrees TrustKay Kendall Leukaemia FundInstituto de Salud Carlos IIINIHR Cambridge Biomedical Research CentreMelanoma Research AllianceNational Institute for Health and Care ResearchWellcome TrustNational Plan for Scientific and Technical Research and Innovation1108-1124.e11https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618647biostudies-literatureUnknown43(6)Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.Cancer cellStromal lipid species dictate melanoma metastasis and tropism.PMC7618647C5759/A27412PI15/01860110078/Z/15/Z825648EP/X033392C5759/A20971C33043/A24478146281KKL1185NIHR203308Ashton GMallela KMotta LBudden TBaker ACraig SMarques JStennett LRomero-Camarero IMarine JCKoulman AAmaral FGurung SSmith DJenkins BGaudy-Marqueste CPozniak JSanz-Moreno Vvon Kriegsheim AFruhwirth GSomervaille TCPZeng KMillan-Esteban DViros AManrique EDurao PNagore EfalseStromal lipid species dictate melanoma metastasis and tropism.Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are still incompletely understood. We show that abundant stromal lipids from young subcutaneous adipocytes, including phosphatidylcholines, are taken up by melanoma cells, where they upregulate melanoma PI3K-AKT signaling, fatty acid oxidation, oxidative phosphorylation (OXPHOS) leading to oxidative stress, resulting in decreased metastatic burden. High OXPHOS melanoma cells predominantly seed the lung and brain; decreasing oxidative stress with antioxidants shifts tropism from the lung to the liver. By contrast, the aged TME provides fewer total lipids but is rich in ceramides, leading to lower OXPHOS and high metastatic burden. Aged TME ceramides taken up by melanoma cells activate the S1P-STAT3-IL-6 signaling axis and promote liver tropism. Inhibiting OXPHOS in the young TME or blocking the IL-6 receptor in the aged TME reduces the age-specific patterns of metastasis imposed by lipid availability.2025-01-01T00:00:00Z2025 Jun2026-06-12T04:56:16.233Z2026-06-12T03:08:22.882ZS-EPMC76186474028012410.1016/j.ccell.2025.04.001