Metabolic reprogramming-a breakthrough point in overcoming resistance to BRAF mutant melanoma targeted therapy (Review).

Targeted therapy for BRAF-mutant melanoma induces metabolic reprogramming, which drives the development of drug resistance. Studies indicate that following treatment with BRAF inhibitors and/or MEK inhibitors, melanoma cells alter metabolic pathways by modifying various regulatory factors. These adaptations include increased lactate accumulation, enhanced oxidative phosphorylation, elevated glutamine utilization via the tricarboxylic acid cycle, activation of the kynurenine pathway and increased fatty acid synthesis. Collectively, these alterations reshape the tumor microenvironment, suppress ferroptosis and activate alternative signaling pathways, thereby conferring resistance to targeted therapy. This paper systematically reviews the mechanisms underlying therapy-induced metabolic reprogramming in BRAF-mutant melanoma and explores potential combinatorial strategies that target these metabolic vulnerabilities alongside established melanoma therapies. Key metabolic targets with promising therapeutic potential identified include lysine-specific demethylase 1, oxidative phosphorylation components, phosphoglycerate dehydrogenase, indoleamine 2,3-dioxygenase 1 and lipid metabolism enzymes such as fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme a reductase.