2. Academic Validation
  3. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

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

  • Nat Commun. 2023 Aug 8;14(1):4758. doi: 10.1038/s41467-023-40518-0.
Ying Xue # 1,  Fujia Lu # 1,  Zhenzhen Chang 1,  Jing Li 1,  Yuan Gao 2,  Jie Zhou 1,  Ying Luo 3,  Yongfeng Lai 1,  Siyuan Cao 1,  Xiaoxiao Li 1,  Yuhan Zhou 1,  Yan Li 1,  Zheng Tan 1,  Xiang Cheng 4,  Xiong Li 5,  Jing Chen 6,  Weimin Wang 7 8 9
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Gynecology & Obstetrics, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. weiminw@hust.edu.cn.
  • 8 Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, China. weiminw@hust.edu.cn.
  • 9 Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. weiminw@hust.edu.cn.
  • # Contributed equally.
PMID: 37553341 DOI: 10.1038/s41467-023-40518-0
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.

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