Table 2.

Molecular mechanism and biological functions of m⁶A in distinct TME of diverse cancers

TME	Regulators	Cancers	Mechanism	Biological functions	References
Hypoxia	METTL3	HCC	methylates FOXO3	promotes sorafenib sensitivity	58
	ALKBH5	BC	demethylates NANOG	promotes specification and maintenance of BCSCs	56
	YTHDF2	HCC	interacts with HIF-2α	suppresses cancer growth	65
Metabolic dysregulation	METTL1	HCC	upregulates PTEN/AKT signaling pathway	promotes malignant phenotype	78
	METTL3	UM	upregulates c-MET, p-AKT, cyclin, and CDK	promotes proliferation and metastasis	79
		GBM	targets PI3K/AKT signaling pathway	suppresses proliferation, migration, and invasiveness	80
	METTL14	EC	regulates expression of PHLPP2 and mTOR2	suppresses proliferation and tumorigenesis	81
		GC	mediates WNT and PI3K/AKT signaling pathway	suppresses proliferation and invasiveness	82
	ALKBH5	EOC	demethylates tRNA	promotes protein synthesis	70
			activates EGFR-PIK3CA-AKT-mTOR signaling pathway	promotes tumor progression	85
	FTO	PAAD	demethylates RUNX1T1	promotes adipogenesis	74,75
			demethylates FOXO1	modulates gluconeogenesis and thermogenesis	50,83
		EC	activates PI3K/AKT and MAPK signaling pathway	promotes tumor cell anabolism and proliferation	84
	YTHDF2	PC	bounds to LHPP and NKX3-1	promotes tumor progression	86
Immune escape	METTL3	TGCT	influences EMT and infiltration of T and NK cells	promotes tumor progression	114
	METTL3/14	CRC	modulates CD8+ T cells, IFN-γ, CXCL9/10 and PD-1	mediates response to immunotherapy	115
	RBM15	PDAC	upregulates APC, MHC I, Th2 cells and Tregs	influences immune responses	111
	ALKBH5	PAAD	modulates CD8+ and CD4+ T cells aggregation	influences immune responses	87
		LUSC	regulates TFH	influences immunotherapy sensitivity	112
			modulates Mct4/Slc16a3 expression, lactate content, Tregs and MDSCs	promotes immune escape	116
	FTO	MM	promotes PD-1L expression	promotes immune escape	69
		AML	upregulates LILRB4 expression	regulates immune escape	117
	YTHDF1	AML	interacts with transcripts of lysosomal proteases	suppresses neoantigen-specific immunity	117
	YTHDF2	AML	mediates decay of LILRB4	regulates immune escape	117
			isolates m6A-circRNA	suppresses innate immunity	118
Chronic inflammatory	METTL3 ALKBH5		modifies ncRNAs	influences carcinogenesis and inflammatory activities	124
	YTHDF2	HCC	promotes decay of IL11	suppresses inflammation, angiogenesis, and metastasis	61

Abbreviations: HCC, human hepatocellular carcinoma; BC, breast cancer; UM, uveal melanoma; GBM, glioblastoma; EC, endometrial cancer; GC, gastric cancer; EOC, epithelial ovarian cancer; PAAD, pancreatic adenocarcinoma; PC, prostate cancer; TGCT, Testicular germ cell tumors; CRC, colorectal cancer; PDAC, pancreatic ductal adenocarcinoma; LUSC, lung squamous cell carcinoma; MM, malignant melanoma; AML, acute myeloid leukemia