Table 1.
m6A modulation under diverse factors in the TIME
| Factor in the TIME | m6A regulator | Cancer type | Molecular mechanism | Effect on tumours and immune surveillance | Reference |
|---|---|---|---|---|---|
| Hypoxia | METTL3 | HCC | HIF-METTL3-FOXO3 axis, enhancing FOXO3 mRNA stabilization by YTHDF1 | Promoting sorafenib resistance | [78] |
| ALKBH5 | BCSC | HIF-ALKBH5-NANOG axis, enhancing NANOG mRNA and protein level | Promoting cancer stem-cell like phenotype and tumorigenesis | [79] | |
| ALKBH5 | ECSC | HIF-ALKBH5-SOX2 axis, enhancing SOX2 transcription | Promoting cancer stem-cell like phenotype and tumorigenesis | [80] | |
| FTO | CRC | Repressing MTA1 mRNA stability by IGF2BP2 | Inhibiting cancer metastasis and progression | [81] | |
| YTHDF1 | HCC | Enhancing ATG2A and ATG14 translation | Enhancing autophagy and autophagy-steered HCC progression | [82] | |
| YTHDF2 | AML | AML1/ETO-HIF1α-YTHDF2 axis, decreasing total m6A level | Promoting cancer proliferation | [83] | |
| YTHDF2 | LUSC | Activating of mTOR/AKT | Promoting tumorigenesis and invasion, inducing EMT | [84] | |
| YTHDF2 | HCC | HIF-2α-YTHDF2, preventing IL-11 and SERPINE2 RNA decay | Inducing inflammation-driven malignancy and disrupting of vascular normalization | [85] | |
| IGF2BP1 | BCSC | Hypoxic lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis, inducing c-Myc mRNA stability | Promotion of self-renewal and tumorigenesis | [86] | |
| IGF2BP3 | SC | Inducing of HIF1A mRNA expression | Retaining HIF-mediated cell migration and angiogenesis | [87] | |
| ALKBH5 | GBM | Enhancing lncRNA NEAT1 transcript stability | Promoting IL8 expression, leading to TAM enrichment and immunosuppressive TIME | [88] | |
| Glycolysis reprogramming | METTL3 | CC | Enhancing HK2 mRNA stability through YTHDF1 | Promoting glycolysis and tumorigenesis | [89] |
| METTL3 | CRC | METTL3/LDHA axis, enhancing LDHA transcription and translation through HIF-1 alfa and YTHDF1, respectively. | Inducing 5-FU chemoresistance | [90] | |
| METTL3 | CRC | Stabilizing transcripts of HK2 and GLUT1 through IGF2BP2, IGF2BP3, respectively | Promoting tumour glycolysis and cancer progression | [91] | |
| METTL3 | CC, HCC | m6A/PDK4 axis, enhancing PDK4 translation and mRNA stability through YTHDF1/eEF-2 and IGF2BP3 | Promoting tumour glycolysis and cancer progression | [92] | |
| METTL3, ALKBH5 | LUAC | Enhancing ENO1 translation through YTHDF1 | Promoting tumour glycolysis and tumorigenesis | [93] | |
| METTL14 | HCC | METTL14-USP48-SIRT6 axis, enhancing USP48 mRNA stability | Attenuating tumour glycolysis and malignancy | [94] | |
| METTL14 | RCC | Repressing BPTF mRNA stability | Inhibiting tumour glycolysis and distal lung metastasis | [95] | |
| METTL14 | GC | Repressing LHPP expression | Promoting tumour glycolysis and cancer progression | [96] | |
| WTAP | BCSC | ERK1/2-WTAP-ENO1, increasing ENO1 mRNA stability | Promoting tumour glycolysis and cancer progression | [97] | |
| WTAP | GC | Enhancing stability of HK2 mRNA | Promoting tumour glycolysis and cancer progression | [98] | |
| KIAA1429 | CRC | Enhancing stability of HK2 mRNA | Promoting tumour glycolysis and cancer progression | [99] | |
| FTO | AML | FTO/PFKP/LDHB axis, upregulating the expression of PFKP and LDHB. | Promoting tumour aerobic glycolysis | [100] | |
| FTO | PTC | Decreasing stability of APOE mRNA by IGF2BP2 | Attenuating tumour glycolysis and cancer growth | [101] | |
| FTO | LUAC | Wnt/β-catenin/FTO/c-Myc, FTO inhibits MYC mRNA translation | Inhibiting tumour glycolysis and tumorigenesis | [102] | |
| ALKBH5 | Bca | Suppressing CK2α mRNA stability | Suppressing tumour glycolysis and cisplatin resistance | [103] | |
| IGF2BP2 | CRC | LINRIS-IGF2BP2-MYC axis, enhancing MYC mRNA stability | Promoting tumour glycolysis and cancer progression | [104] | |
| YTHDF1 | BC | YTHDF1-PKM2, upregulating PKM2 expression | Promoting tumour glycolysis, cancer growth and metastasis | [105] | |
| YTHDF3 | PC | Promoting LncRNA DICER-AS1 degradation | Promoting tumour glycolysis | [106] | |
| YTHDC1 | PDAC | YTHDC1/miR-30d/RUNX1axis, promoting miR-30d and repressing RUNX1. | Attenuating tumour glycolysis and tumorigenesis | [107] | |
| FTO | Melanoma, NSCLC | Enhancing transcripts of c-Jun, JunB, and C/EBPβ | Promoting tumour glycolysis and immune evasion | [108] | |
| YTHDF1 | HCC | CircRHBDD1/YTHDF1/PIK3R1 axis, enhancing PIK3R1 translation | Promoting tumour glycolysis and restraining PD-1 therapy | [109] | |
| Lipid metabolism reprogramming | m6A writer complex, m6A erasers | HCC | m6A methylation negatively regulates CES2 expression by YTHDC2. | m6A methylation augment increased lipid accumulation | [110] |
| METTL3 | HCC | Enhancing lncRNA LINC00958 stability | Promoting lipogenesis and tumour progression | [111] | |
| FTO | EC | Enhancing HSD17B11 expression by YTHDF1 | Promoting lipid droplets and tumour development | [112] | |
| METTL3, METTL14 | CRC | Impairing of RNA decay of DEGS2, promoting DEGS2 levels | Inducing lipid dysregulation, tumour progression | [113] | |
| METTL3 | GBM | Stimulating SLC7A11 mRNA splicing and maturation | Inhibiting ferroptosis | [114] | |
| METTL3 | HB | m6A/IGF2BP1/SLC7A11 axis, preventing SLC7A11deadenylation. | Enhancing ferroptosis resistance | [115] | |
| METTL3 | LUAC | Stabilizing SLC7A11 m6A modification | Promoting tumour growth and inhibiting ferroptosis | [116] | |
| FTO | PTC | Promoting SLC7A11 downregulation | Promoting ferroptosis | [117] | |
| METTL14 | HCC | HIF-1α/METTL14/YTHDF2/SLC7A11 axis, disrupting METTL14 mediated SLC7A11 silencing by YTHDF2 | Inhibiting ferroptosis | [118] | |
| YTHDC2 | LUAC | YTHDC2/HOXA13/SLC3A2 axis, destabilizing HOXA13 mRNA and inhibiting SLC3A2 expression | Inducing ferroptosis | [119] | |
| YTHDF2 | GC | CBSLR/YTHDF2/CBS signalling, decreasing the stability of CBS mRNA and promoting ACSL4 degradation | Inhibiting ferroptosis | [120] | |
| AA metabolism reprogramming | FTO | CRC | FTO/YTHDF2/ATF4, disrupting ATF4 RNA decay by YTHDF2 | Promoting autophagy activation and compromising antitumour effect | [121] |
| FTO | ccRCC | Enhancing SLC1A5 expression | Promoting tumour growth and survival | [122] | |
| YTHDF1 | CRC | Enhancing GLS1 synthesis. | Promoting glutamine uptake and cisplatin resistance | [123] | |
| YTHDF1 | CRC | Dietary methionine and YTHDF1 promotes m6A methylation and translation of PD-L1 and VISTA | Inhibiting antitumour immunity. | [124] | |
| Acidity | ALKBH5 | Melanoma, CRC | Enhancing Mct4 mRNA levels | Enhancing extracellular lactate content and the promoting Treg and MDSC enrichment | [125] |
| METTL3 | CRC | METTL3/m6A/JAK/STAT3 axis, METTL3 lactylation promotes JAK translation. | Promoting immunosuppression of tumour-infiltrating myeloid cells. | [126] | |
| Immune suppression | METTL3 | BCa | JNK/METTL3/PD-L1, enhancing PD-L1 mRNA stability by IGF2BP1 | Promoting tumour immune escape | [127] |
| METTL3 | BC | METTL3/IGF2BP3 axis, promoting stabilization of PD-L1 mRNA | Inhibiting immune surveillance | [128] | |
| METTL3 | NSCLC | YTHDC1/circIGF2BP3, promoting circularization of circIGF2BP3 | Facilitating PD-L1 deubiquitination and promoting immune escape | [129] | |
| METTL14 | CCA | METTL14/Siah2/PD-L1 axis, enhancing Siah2 degradation by YTHDF2 | Inhibiting PD-L1 ubiquitination and immune surveillance | [130] | |
| METTL14 | HCC | METTL14/MIR155HG/PD-L1 axis, stabilizing MIR155HG | Facilitating PD-L1 upregulation and tumour immune escape | [131] | |
| ALKBH5 | ICC | ALKBH5/PD-L1, preventing YTHDF2-mediated PD-L1 RNA decay | Sustaining PD-L1 expression and inhibiting immune surveillance | [132] | |
| ALKBH5 | HNSCC | ALKBH5/RIG-I/IFNα axis, inhibiting mRNA maturation of DDX58 that encodes RIG-1 | Inhibiting RIG-I-mediated IFNα secretion and promoting tumour progression | [133] | |
| FTO | AML | FTO/m6A/LILRB4, enhancing LILRB4 expression | Promoting cancer stem cell self-renewal and immune escape | [134] | |
| FTO | Melanoma | Preventing YTHDF2-mediated mRNA decay of PD-1, CXCR4, SOX10 | Promoting anti-PD-1 resistance | [135] | |
| FTO | OSCC | Promoting the stability and expression of PD-L1 transcripts | Promoting immune resistance and tumour progression | [136] | |
| METTL3 | CRC | m6A-BHLHE41-CXCL1/CXCR2 Axis, increasing CXCR1 transcription through m6A-promoted BHLHE41 expression. | Enhancing MDSCs migration and inhibiting CD8+T cells | [137] | |
| METTL3, YTHDF2 | GBM | Active YY1–CDK9 transcription elongation complex enhanced METTL3, YTHDF2 levels | Promoting immune suppressive TIME | [138] | |
| ALKBH5 | HCC | ALKBH5/MAP3K8 axis, enhancing MAP3K8 expression | Promoting tumour growth, metastasis and PD-L1+macrophage recruitment | [139] |
m6A N6-methyladenosine, HCC Hepatocellular carcinoma, BCSC Breast cancer stem cell, ECSCs Endometrial cancer stem cells, CRC Colorectal cancer, AML Acute mygeeloid leukaemia, LUSC Lung squamous carcinogenesis, SC Stomach cancer, GBM Glioblastoma, CC Cervical cancer, CRC Colorectal cancer, LUAC Lung adenocarcinoma, RCC Renal carcinoma, GC Gastric cancer, PTC Papillary thyroid carcinoma, BCa Bladder cancer, BC Breast cancer, PC Pancreatic cancer, PDAC Pancreatic ductal adenocarcinoma, NSCLC Non-small cell lung carcinoma, EC Esophageal cancer, HB Hepatoblastoma, ccRCC Renal clear cell carcinoma, ICC Intrahepatic cholangiocarcinoma, HNSCC Head and neck squamous cell carcinoma, OSCC Oral squamous cell carcinoma