Cutaneous Melanoma represents the main cause of death among malignant skin neoplasms. Immune checkpoint inhibitors (ICI), such as anti-PD-1 or anti-CTLA-4 blocking antibodies, are successful only in a subset of metastatic melanoma patients due to primary or adaptive resistance mechanisms. Abnormal lipid profiles are often associated with an altered metabolic phenotype in tumor cells, which is a hallmark of cancer. We recently provided evidence that sphingomyelin synthase 1 (SMS1) is frequently downregulated in various solid cancers, more particularly in melanoma. Low SMS1 expression was associated with ceramide metabolism reprogramming and a worse prognosis in metastatic melanoma patients (Bilal et al., Front Pharmacol. 2019). We also identified ceramide metabolism dysregulation [i.e., downregulation of neutral sphingomyelinase 2 (nSMase2) and upregulation of sphingosine kinase 1 (SK1)] in immune escape and resistance to ICI in mouse melanoma models. Reprogramming ceramide metabolism by re-expressing nSMase2 or downregulating SK1 in melanoma cell lines enhances the CD8 T cell-dependent immune response and overcomes the resistance to ICI. Mechanistically, whereas nSMase2 expression increases the small extracellular vesicle immunogenicity, SK1 downregulation reduces the production of key immunosuppressive molecules such as PGE2 and TGF, thus limiting tumor-infiltrating regulatory T lymphocyte content (Montfort et al., Cancer Immunol Res 2021; Imbert et al., Nat Commun., 2020). Interestingly, TNF, which impairs the anti-melanoma immune response (Bertrand et al., Cancer Res. 2015) and confers resistance to ICI in mice (Bertrand et al., Nat Commun. 2017) and possibly in patients (Montfort et al., Clin. Cancer Res. 2021), modulates ceramide metabolism in melanoma cell lines. Ongoing experiments aim at evaluating whether TNF-induced ceramide metabolism changes contribute to melanoma progression and resistance to ICI not only in mice but also in advanced melanoma patients enrolled in prospective clinical trials.