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

Da Teng, Kenneth D. Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R. Avritt, Lei Gu, John M. Asara, Yaqing Zhang and Bin Zheng ()
Additional contact information
Da Teng: Cedars-Sinai Medical Center
Kenneth D. Swanson: Charlestown
Ruiheng Wang: Cedars-Sinai Medical Center
Aojia Zhuang: Cedars-Sinai Medical Center
Haofeng Wu: Charlestown
Zhixin Niu: Max Planck Institute for Heart and Lung Research
Li Cai: University of Texas MD Anderson Cancer Center
Faith R. Avritt: University of Michigan
Lei Gu: Max Planck Institute for Heart and Lung Research
John M. Asara: Boston
Yaqing Zhang: University of Michigan
Bin Zheng: Cedars-Sinai Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59307-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59307-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59307-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().