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

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 and Weimin Wang ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40518-0

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