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

Author

Listed:
  • Da Teng

    (Cedars-Sinai Medical Center
    Charlestown)

  • Kenneth D. Swanson

    (Charlestown)

  • Ruiheng Wang

    (Cedars-Sinai Medical Center
    Charlestown)

  • 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
    Charlestown)

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.

Suggested Citation

  • 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 & Bin Zheng, 2025. "DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59307-y
    DOI: 10.1038/s41467-025-59307-y
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    References listed on IDEAS

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    1. Inmaculada Martínez-Reyes & Luzivette Robles Cardona & Hyewon Kong & Karthik Vasan & Gregory S. McElroy & Marie Werner & Hermon Kihshen & Colleen R. Reczek & Samuel E. Weinberg & Peng Gao & Elizabeth , 2020. "Mitochondrial ubiquinol oxidation is necessary for tumour growth," Nature, Nature, vol. 585(7824), pages 288-292, September.
    2. Eikan Mishima & Toshitaka Nakamura & Jiashuo Zheng & Weijia Zhang & André Santos Dias Mourão & Peter Sennhenn & Marcus Conrad, 2023. "DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition," Nature, Nature, vol. 619(7968), pages 9-18, July.
    3. Weimin Wang & Michael Green & Jae Eun Choi & Miguel Gijón & Paul D. Kennedy & Jeffrey K. Johnson & Peng Liao & Xueting Lang & Ilona Kryczek & Amanda Sell & Houjun Xia & Jiajia Zhou & Gaopeng Li & Jing, 2019. "CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy," Nature, Nature, vol. 569(7755), pages 270-274, May.
    4. Chao Mao & Xiaoguang Liu & Yuelong Yan & Kellen Olszewski & Boyi Gan, 2023. "Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition," Nature, Nature, vol. 619(7968), pages 19-23, July.
    5. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Chao Mao & Xiaoguang Liu & Yilei Zhang & Guang Lei & Yuelong Yan & Hyemin Lee & Pranavi Koppula & Shiqi Wu & Li Zhuang & Bingliang Fang & Masha V. Poyurovsky & Kellen Olszewski & Boyi Gan, 2021. "DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer," Nature, Nature, vol. 593(7860), pages 586-590, May.
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