Review Volume 15, Issue 9 pp 3857—3889

Insights into N6-methyladenosine (m6A) modification of noncoding RNA in tumor microenvironment

YanJun Zhang1, , Lijuan Zhan1, , Jing Li1, , Xue Jiang1, , Li Yin2,3, ,

  • 1 College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
  • 2 Department of Biopharmaceutics, Yulin Normal University, Guangxi, Yulin 537000, China
  • 3 Bioengineering and Technology Center for Native Medicinal Resources Development, Yulin Normal University, Yulin 537000, China

Received: August 25, 2022       Accepted: April 15, 2023       Published: May 12, 2023
How to Cite

Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.


TME: Tumor microenvironment; m6A: N6-methyladenosine; ncRNAs: non-coding RNAs; ECM: extracellular matrix; UTR: untranslated region; EMT: epithelial-mesenchymal transition; CAFs: cancer-associated fibroblasts; TGF-β: Transforming growth factor β; PDGFs: platelet-derived growth factors; FGF: fibroblast growth factor; SDF-1: Stromal derived factor 1; ECs: endothelial cells; lncRNA: long non-coding RNA; VEGF: vascular endothelial growth factor; MAPK: mitogen-activated protein kinase; MDSCs: myeloid derived suppressor cells; IL: interleukin; GM-CSF: granulocyte macrophage colony stimulating factor; TAMs: Tumor-associated macrophages; MMP: matrix metalloproteinases; DCs: Dendritic cells; pDCs: plasmacytoid dendritic cells; mDCs: myeloid dendritic cells; Th: T helper; CTL: cytotoxic T lymphocytes; TILs: tumor infiltrating lymphocytes; HCC: hepatocellular carcinoma; CTLA-4: cytotoxic T lymphocyte-associated antigen-4; PD-1: programmed death-1; ICIs: Immunocheckpoint inhibitors; Tregs: regulatory T cells; IFN: Interferon; SAM: S-adenosylmethionine; METTL3: methyltransferase-like 3; METTL14: methyltransferase-like 14; WTAP: Wilms’ tumor1-associating protein; METTL16: methyltransferase-like 16; RBM15: RNA binding motif protein 15; ZC3H13: Zinc finger CCCH domain-containing protein 13; FTO: obesity-associated genes; ALKBH5: AlkB homolog 5; YTHDF: YTH Domain family; YTHDC: YTH domain-containing proteins; HNRNP: heterogeneous nuclear ribonucleoproteins; eIF3: eukaryotic translation initiation factor 3; IGF2BP1/2/3: insulin-like growth factor 2 mRNA-binding protein 1/2/3; DGCR8: DiGeorge Critical Region 8; SNPs: single nucleotide polymorphisms; AML: acute myeloid leukemia; PDAC: pancreatic ductal adenocarcinoma; GC: gastric cancer; RISC: RNA-induced silencing complex; pri-miRNAs: primary miRNAs; pre-miRNAs: precursor miRNAs; IRES: internal ribosomal entry site; CRC: colorectal cancer; NSCLC: non-small cell lung cancer; GSCs: glioblastoma stem cell-like cells; hucMSC: human umbilical cord mesenchymal stem cell; NP: nucleus pulposus; IVDD: intervertebral disc degeneration; FSP1: fibroblast secretory protein 1; DCA: Deoxycholic acid; GBC: gallbladder cancer; MVB: multivesicular bodies; ESCC: esophageal squamous cell carcinoma; CSC: cancer stem cells; RCC: renal cell carcinoma; HUVECs: human umbilical vein endothelial cells; PC: Pancreatic cancer; sEV: Small extracellular vesicles; KCs: Kupffer cells; hBMSCs: human bone marrow-derived mesenchymal stem cells; GBM: glioblastoma; DLNs: draining lymph nodes; HNSCC: head and neck squamous cell carcinoma; EOC: epithelial ovarian cancer; KIRC: kidney renal clear cell carcinoma; AUC: area under the ROC curve; HGG: high-grade glioma; LGG: low-grade glioma; CIS-R: cisplatin-resistant; CIS-S: cisplatin-sensitive; PR: partial responses; SD: stable disease; PDX: patient-derived xenograft.