Table 1 m⁶A modulation under diverse factors in the TIME

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]