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<p>Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.</p>

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Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Yuhan Zhou,
  • Jing Li,
  • Fangfang Liu,
  • Yuan Gao,
  • Songlin Yin,
  • Liguo Yang,
  • Xiaoxiao Li,
  • Junhong Lin,
  • Yan Li,
  • Haotian Shang,
  • Xiang Cheng,
  • Tengfei Chao,
  • Qian Chu,
  • Fujia Lu,
  • Weimin Wang

摘要

Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.