An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma.

ABSTRACT:

Background

Metabolic 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.

Methods

To 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 mo

SUBMITTER: Hai Y 

PROVIDER: S-EPMC12619403 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature