DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis

  • Nat Commun. 2025 Apr 24;16(1):3867. doi: 10.1038/s41467-025-59307-y.
Da Teng  1  2 ,  Kenneth D Swanson  2 ,  Ruiheng Wang  1  2 ,  Aojia Zhuang  1 ,  Haofeng Wu  2 ,  Zhixin Niu  3 ,  Li Cai  4 ,  Faith R Avritt  5 ,  Lei Gu  3 ,  John M Asara  6 ,  Yaqing Zhang  7 ,  Bin Zheng  8  9
Affiliations
  • 1. Cedars-Sinai Cancer Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, USA.
  • 2. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
  • 3. Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 4. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, USA.
  • 6. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  • 7. Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 8. Cedars-Sinai Cancer Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, USA. [email protected].
  • 9. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. [email protected].
PMID: 40274823 DOI: 10.1038/s41467-025-59307-y
Abstract

The ability of Cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of Dihydroorotate Dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases Cancer cell sensitivity to T cell cytotoxicity through induction of Ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in Cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of Cancer immunotherapies.

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