Targeting the N6-Methyladenosine Pathway for Cancer Immunotherapy

Immune cells, derived from hematopoietic stem cells, undergo a series of cell stage transitions tightly regulated by dynamic changes in the transcriptome. Rapid transcriptome changes also allow for precise immune responses in different contexts. Extensive studies have attributed the transcriptome changes to the activity of transcription factors. However, my doctoral work revealed the role of N6-methyladenosine (m6A) modifications in assisting these rapid transcriptome changes in immune cells. In developing B cells, we discovered that m6A modifications on mRNAs accelerate the decay through recognition by m6A binding protein, YTHDF2, during the transition from pro-B cell to large pre-B cell and pre-B cell proliferation. Additionally, in intratumoral regulatory T (Treg) cells, m6A modifications on transcripts of NF-kB negative regulators indirectly perturb NF-kB mediated transcription to impact immune response in the tumor microenvironment. The discovery of these regulatory mechanisms highlights the m6A pathway as a promising target for manipulating immune cell function and enhancing anti-tumor immune response. To further explore the therapeutic potentials, we initiated a study to identify small molecule inhibitors of YTHDF2. Successful inhibitors targeting the m6A pathway would have tremendous clinical value.