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Background <p>Metabolic reprogramming, particularly upregulated <i>de novo</i> 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.</p> Methods <p>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 models, including standard and neoadjuvant settings.</p> Results <p>H62 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.</p> Conclusions <p>This 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.</p>

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An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Yongrui Hai,
  • Wenhui Wang,
  • Renming Fan,
  • Ye Chen,
  • Junyan Zhuang,
  • Shuo Fu,
  • Guiquan Ding,
  • Lei Liang,
  • Junke Song,
  • Gaofei Wei

摘要

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 models, including standard and neoadjuvant settings.

Results

H62 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.

Conclusions

This 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.