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- Title
Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade.
- Authors
Xue, Ying; Lu, Fujia; Chang, Zhenzhen; Li, Jing; Gao, Yuan; Zhou, Jie; Luo, Ying; Lai, Yongfeng; Cao, Siyuan; Li, Xiaoxiao; Zhou, Yuhan; Li, Yan; Tan, Zheng; Cheng, Xiang; Li, Xiong; Chen, Jing; Wang, Weimin
- 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. The application of dietary methionine intervention is of particular interest in the field of cancer therapy. Here the authors show that intermittent but not sustained deprivation of methionine promotes tumor ferroptosis and improves response to checkpoint inhibitors.
- Subjects
METHIONINE; ION transport (Biology); CELL-mediated cytotoxicity; PROGRAMMED cell death 1 receptors; SLEEP deprivation; CANCER chemotherapy; PROTEIN synthesis; T cells
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40518-0