S1P signaling drives cancer metastasis by activating STAT3 and IL-6 production.42 Therefore, we tested whether ceramides in the aged TME drive metastatic spread and liver tropism via the S1P-STAT3-IL-6 signaling axis, and confirmed that SPHK1 expression, a critical gene in the S1P pathway, was increased in OA-melanoma cells and aged-MFP-melanomas compared to YA-melanoma and young-MFP-melanomas (Figures S6F and S6G; Table S4). Here, SPHK1 is linked to melanoma.