ArticleJournal of experimental & clinical cancer research : CR2025
An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMetabolic reprogramming, particularly upregulated de novo pyrimidine biosynthesis, drives cancer progression and immune evasion. Dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, is a promising therapeutic target, but its inhibitors often face resistance in immune-refractory melanoma, linked to low basal stimulator of interferon genes (STING) expression.
methodsTo overcome this limitation, we designed H62, a tumor-selective prodrug conjugating the DHODH inhibitor EA6 with the STING agonist MSA-2 via a cathepsin B-cleavable linker. Mechanistic studies evaluated mitochondrial disruption, pyroptosis (caspase-3/GSDME), and STING-mediated interferon signaling, alongside natural killer (NK) cell recruitment. Efficacy was tested in multiple melanoma models, including standard and neoadjuvant settings.
resultsH62 synergistically induced mitochondrial dysfunction and pyroptosis while activating STING/type I interferon responses, enhancing NK cell cytotoxicity. In melanoma models, it significantly suppressed tumor growth, reduced postoperative recurrence, and improved survival.
conclusionsThis dual-targeting strategy overcomes DHODH inhibitor resistance by coupling metabolic interference with innate immune activation, offering translational potential for melanoma and other treatment-resistant cancers.
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