N6 -methyladenosine (m6 A), the newest and most prevalent layer of internal epigenetic modification in eukaryotic mRNA, has been demonstrated to play a critical role in cancer biology. Increasing evidence has highlighted that the interaction between cancer stem cells (CSCs) and the tumor immune microenvironment (TIME) is the root cause of tumorigenesis, metastasis, therapy resistance, and recurrence. In recent studies, the m6 A modification has been tightly linked to this CSC-TIME interplay, participating in the regulation of CSCs and TIME remolding. Interestingly, the m6 A modification has also been identified as a novel decisive factor in the efficacy of immunotherapies-particularly anti-PD-1/PD-L1 monotherapies-by changing the plasticity of the TIME. Given the functional importance of the m6 A modification in the crosstalk between CSCs and the TIME, targeting m6 A regulators will open new avenues to overcome therapeutic resistance, especially for immune checkpoint-based immunotherapy. In the present review, we summarize the current landscape of m6 A modifications in CSCs and the TIME, and also prospect the underling role of m6 A modifications at the crossroads of CSCs and the TIME for the first time. Additionally, to provide the possibility of modulating m6 A modifications as an emerging therapeutic strategy, we also explore the burgeoning inhibitors and technologies targeting m6 A regulators. Lastly, considering recent advances in m6 A-seq technologies and cancer drug development, we propose the future directions of m6 A modification in clinical applications, which may not only help to improve individualized monitoring and therapy but also provide enhanced and durable responses in patients with insensitive tumors.
Keywords: PD-1; PD-L1; cancer stem cells; immune checkpoint; immunotherapy; m6A modification; metastasis; recurrence; therapeutic resistance; tumor immune microenvironment.
© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.