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Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

Author

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  • Ying Xue

    (Huazhong University of Science and Technology)

  • Fujia Lu

    (Huazhong University of Science and Technology)

  • Zhenzhen Chang

    (Huazhong University of Science and Technology)

  • Jing Li

    (Huazhong University of Science and Technology)

  • Yuan Gao

    (Huazhong University of Science and Technology)

  • Jie Zhou

    (Huazhong University of Science and Technology)

  • Ying Luo

    (Huazhong University of Science and Technology)

  • Yongfeng Lai

    (Huazhong University of Science and Technology)

  • Siyuan Cao

    (Huazhong University of Science and Technology)

  • Xiaoxiao Li

    (Huazhong University of Science and Technology)

  • Yuhan Zhou

    (Huazhong University of Science and Technology)

  • Yan Li

    (Huazhong University of Science and Technology)

  • Zheng Tan

    (Huazhong University of Science and Technology)

  • Xiang Cheng

    (Huazhong University of Science and Technology)

  • Xiong Li

    (Huazhong University of Science and Technology)

  • Jing Chen

    (Huazhong University of Science and Technology)

  • Weimin Wang

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Chinese Academy of Medical Sciences)

Abstract

Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonged methionine deprivation prevents glutathione (GSH) depletion from exceeding the death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis. Intermittent methionine deprivation also sensitizes tumor cells against CD8+ T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation. Clinically, tumor CHAC1 correlates with clinical benefits and improved survival in cancer patients treated with checkpoint blockades. Lastly, the triple combination of methionine intermittent deprivation, system xc- inhibitor and PD-1 blockade shows superior antitumor efficacy. Thus, intermittent methionine deprivation is a promising regimen to target ferroptosis and augment cancer immunotherapy.

Suggested Citation

  • Ying Xue & Fujia Lu & Zhenzhen Chang & Jing Li & Yuan Gao & Jie Zhou & Ying Luo & Yongfeng Lai & Siyuan Cao & Xiaoxiao Li & Yuhan Zhou & Yan Li & Zheng Tan & Xiang Cheng & Xiong Li & Jing Chen & Weimi, 2023. "Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40518-0
    DOI: 10.1038/s41467-023-40518-0
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    1. Chaoyi Xia & Pinghui Peng & Wenxia Zhang & Xiyue Xing & Xin Jin & Jianlan Du & Wanting Peng & Fengqi Hao & Zhexuan Zhao & Kejian Dong & Miaomiao Tian & Yunpeng Feng & Xueqing Ba & Min Wei & Yang Wang, 2024. "Methionine-SAM metabolism-dependent ubiquinone synthesis is crucial for ROS accumulation in ferroptosis induction," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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