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

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. Inducing ferroptosis enhances the response to cancer immunotherapy. Here, the authors show that disrupting fatty acid oxidation at the HADHA node promotes tumor ferroptosis via accumulation of the intermediate C18-OH. Consequently, the clinically approved HADHA inhibitor trimetazidine promotes ferroptosis and potentiates immunotherapeutic efficacy.