The emerging role of metabolic interventions in uveal melanoma

Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults, presenting significant clinical challenges due to its aggressive nature and metastatic potential, which results in poor prognosis in some patients. Despite recent therapeutic advances, the survival rate for metastatic UM remains unsatisfactory, underscoring the need for innovative intervention strategies. A promising direction involves the exploitation of differentially activated metabolic pathways, which are increasingly recognized for their crucial roles in cancer cell growth and metastasis. UM exhibits significant metabolic plasticity, enabling adaptation to microenvironmental stresses. While solid tumors often depend on glycolysis for energy-a phenomenon known as the Warburg effect-recent studies highlight the role of mitochondrial oxidative phosphorylation (OXPHOS), glutaminolysis, as well as fatty acid oxidation (FAO) in UM progression and therapy resistance. The observed diversity in metabolic reliance suggests that targeting metabolic plasticity-either alone or in combination with current treatments-may represent an effective therapeutic strategy. Emerging research connects the metabolic profile of UM cells to genetic and epigenetic changes, including through oncogenic pathways driven by GNAQ and GNA11 mutations, which affect mitochondrial function and energy metabolism. This metabolic reprogramming may confer survival advantages, particularly in the nutrient- and oxygen-limited ocular environment. Here, we review recent advances on how molecular aberrations in UM alter cancer cell metabolic and mitochondrial functions, and whether these represent opportunities for therapeutic targeting. Furthering our understanding of the specific metabolic and mitochondrial changes that drive UM progression and metastasis will lead to the discovery of novel metabolic and mitochondrial biomarkers for early diagnosis, prognosis, and treatment guidance, ultimately enabling the development of more effective therapeutic strategies that exploit the unique metabolic vulnerabilities of UM cells.