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

  • Nat Commun. 2026 Jun 17. doi: 10.1038/s41467-026-74430-0.
Yuhan Zhou  #  1 ,  Jing Li  #  1  2 ,  Fangfang Liu  #  3 ,  Yuan Gao  3 ,  Songlin Yin  1 ,  Liguo Yang  1 ,  Xiaoxiao Li  1 ,  Junhong Lin  1 ,  Yan Li  1 ,  Haotian Shang  3 ,  Xiang Cheng  4 ,  Tengfei Chao  5 ,  Qian Chu  6 ,  Fujia Lu  7 ,  Weimin Wang  8  9  10  11  12
Affiliations
  • 1. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Key Laboratory of Fermentation Engineering (Ministry of Education), National "111" Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Hubei University of Technology, Wuhan, China.
  • 3. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 6. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 7. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 9. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 10. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 11. Hubei key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China. [email protected].
  • 12. Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 42310293 DOI: 10.1038/s41467-026-74430-0
Abstract

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.

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