RNA N6-methyladenosine modification in the lethal teamwork of cancer stem cells and the tumor immune microenvironment: Current landscape and therapeutic potential

N-6-methyladenosine (m(6)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 m(6)A modification has been tightly linked to this CSC-TIME interplay, participating in the regulation of CSCs and TIME remolding. Interestingly, the m(6)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 m(6)A modification in the crosstalk between CSCs and the TIME, targeting m(6)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 m(6)A modifications in CSCs and the TIME, and also prospect the underling role of m(6)A modifications at the crossroads of CSCs and the TIME for the first time. Additionally, to provide the possibility of modulating m(6)A modifications as an emerging therapeutic strategy, we also explore the burgeoning inhibitors and technologies targeting m(6)A regulators. Lastly, considering recent advances in m(6)A-seq technologies and cancer drug development, we propose the future directions of m(6)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.