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

Ever-increasing understanding about 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 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. B16-OVA-shNC and shFto cells were used to generate libraries of RNA-seq and ATAC-seq. B16-OVA-shNC, shFto and Dac51 treated shNC cells were used to generate libraries of m6A-seq. OTI CD8+ T cells co-cultured with B16-OVA-shNC or B16-OVA-shFto were sorted to generate libraries for RNA-seq.