Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

Yi Liu; Guanghao Liang; Hongjiao Xu; Wenxin Dong; Ze Dong; Zhiwei Qiu; Zihao Zhang; Fangle Li; Yue Huang; Yilin Li; Jun Wu; Shenyi Yin; Yawei Zhang; Peijin Guo; Jun Liu; Jianzhong Jeff Xi; Peng Jiang; Dali Han; Cai-Guang Yang; Meng Michelle Xu

doi:10.1016/j.cmet.2021.04.001

Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

Cell Metab. 2021 Jun 1;33(6):1221-1233.e11. doi: 10.1016/j.cmet.2021.04.001. Epub 2021 Apr 27.

Authors

Yi Liu¹, Guanghao Liang², Hongjiao Xu³, Wenxin Dong¹, Ze Dong³, Zhiwei Qiu¹, Zihao Zhang¹, Fangle Li², Yue Huang⁴, Yilin Li¹, Jun Wu⁵, Shenyi Yin⁶, Yawei Zhang², Peijin Guo¹, Jun Liu⁷, Jianzhong Jeff Xi⁶, Peng Jiang⁵, Dali Han⁸, Cai-Guang Yang⁹, Meng Michelle Xu¹⁰

Affiliations

¹ Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing 100084, China.
² Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
⁵ Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁶ State Key Laboratory of Natural and Biomimetic Drugs, Institute of Molecular Medicine, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
⁷ Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
⁸ Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; China National Center for Bioinformation, Beijing 100101, China. Electronic address: handl@big.ac.cn.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: yangcg@simm.ac.cn.
¹⁰ Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: michellexu@mail.tsinghua.edu.cn.

PMID: 33910046
DOI: 10.1016/j.cmet.2021.04.001

Abstract

The ever-increasing understanding of the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the m⁶A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m⁶A demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8⁺ T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound, Dac51, that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.

Keywords: RNA m6A modification; demethylase FTO; epitranscriptome; glycolytic metabolism; immune surveillance and immunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO / immunology*
Animals
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic*
Immunologic Surveillance*
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Neoplasms / immunology*

Substances

FTO protein, mouse
Alpha-Ketoglutarate-Dependent Dioxygenase FTO