Melanoma has long served as a paradigm for cancer immunotherapy due to its high immunogenicity and the transformative impact of immune checkpoint blockade. However, durable clinical benefit remains confined to a subset of patients, with primary and acquired resistance remaining common. This plateau highlights a central unresolved question: how melanoma evades immune-mediated elimination despite reinvigorated antitumor immunity. Immune escape in melanoma cannot be fully explained by defects in antigen presentation, interferon signaling, or checkpoint regulation alone. Increasing evidence identifies tumor-intrinsic metabolic reprogramming as a dominant driver of immune dysfunction. By rewiring glucose, amino acid, lipid, and mitochondrial metabolism, melanoma cells create a metabolically restrictive microenvironment that suppresses effector T and NK cell function while favoring regulatory and myeloid immunosuppressive states through nutrient competition, inhibitory metabolite accumulation, and metabolite-driven signaling. In this Review, we synthesize recent advances establishing metabolic reprogramming as an organizing principle of immune escape in melanoma. We integrate how tumor metabolic programs shape immune cell fate, function, and spatial organization, and how metabolic crosstalk between tumor and immune compartments generates immune-resistant niches that persist despite checkpoint blockade. We further discuss emerging therapeutic strategies that target metabolic vulnerabilities, alone or in rational combination with immunotherapy, to overcome resistance by reconditioning the metabolic context of antitumor immunity. By reframing metabolism as a governing axis rather than a secondary hallmark of melanoma, this Review provides a conceptual and translational framework for the development of mechanism-guided immunotherapies with durable clinical impact.
Liang et al. (2026) studied this question.