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

Abstract

N6‐methyladenosine (m6A), 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 m6A modification has been tightly linked to this CSC‐TIME interplay, participating in the regulation of CSCs and TIME remolding. Interestingly, the m6A 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 m6A modification in the crosstalk between CSCs and the TIME, targeting m6A 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 m6A modifications in CSCs and the TIME, and also prospect the underling role of m6A modifications at the crossroads of CSCs and the TIME for the first time. Additionally, to provide the possibility of modulating m6A modifications as an emerging therapeutic strategy, we also explore the burgeoning inhibitors and technologies targeting m6A regulators. Lastly, considering recent advances in m6A‐seq technologies and cancer drug development, we propose the future directions of m6A 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.

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

“…In addition, m6A methyltransferase complex is mainly composed of METTL3 (methyltransferase-like 3), METTL14 (methyltransferase-like 14), and WTAP (Wilms tumor 1-associated protein), which act as "writer" to catalyze methylation processes, whereas FTO (fat mass and obesity associated protein) and ALKBH5 (alkB homolog 5) act as demethylases ("eraser"). The ultimate fate of m6A methylated mRNA depends on the "reader" (e.g., YTHDF1, YTHDF2, and YTHDF3) that recognizes them, affecting mRNA translation, stability, splicing, and nuclear transportation (7). Numerous m6A targets have been involved in cell tissue development and stem cell self-renewal and differentiation, circadian rhythm regulation, T-cell homeostasis, mouse fertility, postnatal development of the mouse cerebellum, innate immune response, ultraviolet-induced DNA damage response, and dendritic cell antigen presentation (8)(9)(10).…”

m6A Regulator-Mediated Methylation Modification Patterns and Characterisation of Tumour Microenvironment Infiltration in Non-Small Cell Lung Cancer

“…Several studies have demonstrated a strong correlation between TME and m 6 A modifications, especially in immune cell infiltration. 33 , 34 ALKBH5 modulates the therapeutic response of anti-PD-1 by regulating lactate and inhibiting the accumulation of immune cells in TIME, thereby reducing the outcome of immunotherapy in melanoma, colorectal cancer and potentially other cancers. 35 FTO enhances protein expression by regulating the m 6 A modification of JUNB and CEBPB genes, thereby promoting tumour glycolysis and inhibiting T cell effects.…”

Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA

“…This modification is regulated by the m6A methyltransferases (writers) methyltransferase-like 3 (METTL3), METTL14, METTL16, Zinc finger CCCH domain-containing protein 13 (ZC3H13), and Homo sapiens RNA binding motif protein 15 (RBM15); demethylases (erasers) fat mass- and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5); and binding proteins (readers) YTH domain family (YTHDF) proteins such as YTHDF1-3 and YTHDC1-2, and insulin-like growth factor 2 messenger RNA-binding proteins (IGF2BP1-3) [ 8 ]. These proteins are frequently upregulated or downregulated in human cancer tissues to control cell differentiation via altering splicing, RNA processing, protein translation, microRNA binding, and RNA-protein interaction [ 9 ]. For example, METTL14-dependent m6A methylation-mediated hepatocyte nuclear factor 3γ mRNA reduction rendered hepatocellular carcinoma dedifferentiation [ 10 ].…”