Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond

Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.