CD8⁺ T cells are the key immune cells to recognize and eliminate tumor cells, but their functions are usually inhibited by the immunosuppressive tumor microenvironment. Previous studies have shown that tumor cells utilize diverse epigenetic mechanisms to evade T cell-mediated immune surveillance.

As a dynamic and reversible modification of the epitranscriptome, m⁶A modification affects the RNA stability and translation processes, playing an important role in the occurrence and progress of tumors. However, how m⁶A modifications participate in regulating the tumor immune microenvironment and regulating T cell-mediated immune surveillance is still unclear.

In a study published in Cell Metabolism, a team led by Prof. HAN Dali from Beijing Institute of Genomics of the Chinese Academy of Sciences (China National Center for Bioinformation), Prof. XU Michelle Meng from Tsinghua University, and Prof. YANG Caiguang from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, revealed that the m⁶A demethylase FTO could enhance the glycolytic metabolism of tumor cells through epitranscriptomic regulation, thereby inhibiting T cell activation and promoting immune evasion.

The researchers found that knocking down the m⁶A demethylase FTO in various solid tumors can inhibit tumor growth in mice and increase the proportion of tumor-infiltrating antigen-specific CD8⁺ T cells, and showed that knocking down FTO in tumors leads to faster activation of CD8⁺ T cells, promoting their antitumor capability.

Through integrated analysis of multidimensional omics sequencing data, including RNA-seq, MeRIP-seq (m⁶A-seq), ATAC-seq, ChIP-seq, they found that FTO can specifically remove the m⁶A modification on mRNA transcripts of multiple bZIP family transcription factors, thus facilitating their mRNA stability. These bZIP family transcription factors can promote the expression of glycolytic genes and enhance the glycolytic activity of tumor cells, which in turn inhibits the activation of CD8⁺ T cells.

Besides, the researchers used the small molecule inhibitor Dac51 that targets FTO to further verify the mechanism of FTO in regulating glycolysis metabolism and escaping immune surveillance.

They conducted PD-L1 blockade and Dac51 treatment in tumor-bearing mice model, and found that both can effectively inhibit tumor growth in mice, while the combination of PD-L1 and Dac51 can greatly improve the therapeutic effect. Also, they found that Dac51 treatment can also effectively enhance the antitumor immune response of T cells in patient-derived organoid model, suggesting the possibility of Dac51 in clinical applications.

This study uncovers that RNA epitranscriptome can be operating as an additional layer of genetic regulation for immune evasion, which would facilitate the discovery of a new class of potentially vulnerable epitranscriptomic immunotherapy targets.