Background <p>Melanoma is a highly lethal skin cancer arising from the malignant transformation of melanocytes. Dysregulated lipid metabolism is the hallmark of cancer. Some recent reports have revealed that lipid metabolism-related genes can be used to predict the prognosis of patients with cancer and regulate tumor immune microenvironment, whereas the role and underlying mechanism in melanoma remains elusive.</p> Methods <p>Data from the TCGA and GEO databases were leveraged to define molecular subgroups by different lipid metabolism status through consensus clustering. The tumor immune microenvironment (TIME) composition in these subgroups of melanoma patients was assessed through ssGSEA, TIMER, and ESTIMATE approaches. The LASSO algorithm and multivariate Cox regression analyses were employed to develop a prognostic risk model. Animal experiments and a panel of biochemical assays were employed to investigate the effect of crucial lipid metabolism molecules on ferroptosis and immunotherapy efficacy.</p> Results <p>In this study, two subgroups of melanoma patients with distinct lipid metabolism-related gene profile exhibited differential survival outcomes and characteristics of anti-tumor immunity. Subsequently, a lipid metabolism-related gene-based risk model was constructed and a nomogram based on the combination of this model and patient clinical characteristics was developed to provide reliable prognostic estimates. Furthermore, we proved that lipid metabolism-related gene ACSL4 can regulate ferroptosis and immunotherapy response in melanoma.</p> Conclusion <p>Lipid metabolism-related gene signature is closely associated with TIME composition in melanoma and could be used to assess the survival of patients. The intervention of ACSL4 expression could be taken into consideration for the improvement of melanoma immunotherapy in the future.</p>