Journal
CELL METABOLISM
Volume 33, Issue 6, Pages 1221-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.04.001
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Funding
- Beijing Natural Science Foundation [Z200023]
- Strategic Priority Research Program [XDA16010115]
- National Natural Science Foundation of China [81922054, 21725801, 31922017, 91853132, 21807103, 21907101]
- National Key R&D Program of China [2016YFA0501500, 2018YFA0109700]
- Key Research Program of Frontier Sciences, Chinese Academy of Sciences [ZDBS-LY-SM013]
- CAS Hundred Talent Program
- Science and Technology Commission of Shanghai Municipality [18431907100, 18YF1428500]
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Research has identified the m(6)A demethylase FTO as a key regulator in tumors, impacting immune surveillance through glycolytic metabolism regulation. Knockdown of FTO impairs tumor cell glycolytic activity, restores CD8(+) T cell function, and inhibits tumor growth. Additionally, the development of the small-molecule compound Dac51 can block FTO-mediated immune evasion and synergize with checkpoint blockade for improved tumor control.
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 m(6)A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m(6)A demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBP beta, 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.
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