Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Zhang, Fusheng; Liu, Haiyang; Duan, Meiqi; Wang, Guang; Zhang, Zhenghou; Wang, Yutian; Qian, Yiping; Yang, Zhi; Jiang, Xiaofeng

doi:10.1186/s13045-022-01304-5

Table 1 Involvement of m⁶A methylation in regulation of tumor proliferation through TME

From: Crosstalk among m⁶A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

TME	m⁶A regulator	Tumor type	Mechanism	Effect on tumor progression	References
Hypoxia	METTL3	HCC	Methylates FOXO3	RNA m⁶A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy	[202]
Hypoxia	ALKBH5	Breast cancer	Hypoxia mediates NANOG mRNA m⁶A-demethylation through HIF dependence and ALKBH5	Induces breast cancer stem cell phenotype and accelerates tumor cell proliferation	[166]
Hypoxia	METTL3	HCC	Induces upregulation of HIF-1α and maintenance of higher levels of glycolysis in hypoxia by positively promoting expression of the m⁶A methyl esterase METTL3	Promotes malignant biological behavior in hepatocellular carcinoma	[33]
Hypoxia	YTHDF2	Lung cancer	Hypoxia-induced SUMOylation of YTHDF2 at the major site of K571 significantly enhances its binding affinity to m⁶A methylation-modified mRNA, leading to dysregulation of gene	Promoting the progression of lung cancer	[307]
Hypoxia	ALKBH5	Glioblastoma	Hypoxia-induced ALKBH5 eliminates m⁶A methylated lncRNA NEAT1 deposition, stabilizes transcripts and promotes NEAT1-mediated paraspeckle assembly, resulting in secretion of the immunosuppressive factor CXCL8/IL8	Shapes the immunosuppressive TME through TAM recruitment and supports immune escape in glioblastoma	[32]
Metabolic	FTO	HCC	FTO triggers the demethylation of PKM2 mRNA and accelerates translation	Promotes hepatocellular carcinoma	[62]
Metabolic	IGF2BP2	Colorectal cancer	Overexpression of the m⁶A methylation reader IGF2BP2 stabilizes the ZFAS1/OLA1 axis and increases OLA1 recruitment, ATP hydrolysis and glycolysis	Promotes colorectal cancer cell invasion and colony formation by activating the Warburg effect	[65]
Metabolic	METTL1	HCC	Upregulates PTEN/AKT signaling	Promotes HCC growth, resulting in poor prognosis	[308]
Metabolic	METTL3	Uveal melanoma	Upregulates c-Met, p-AKT, cyclin and CDK	Promotes tumor cell metastasis and invasion	[309]
Metabolic	YTHDF2	Prostate cancer	Binds to LHPP and NKX3-1	Promotes tumor growth	[310]
Metabolic	ALKBH5	Ovarian cancer	Activates EGFR-PIK3CA-AKT-mTOR	Promotes tumor proliferation	[311]
Metabolic	METTL3/YTHDF2	NA	METTL3 promotes YTHDF2 binding to PPaRα through m⁶A modification to increase its mRNA stability	Increases lipid accumulation in cells	[85]
Immune escape	ALKBH5	Pancreatic cancer	Modulates CD8⁺ and CD4⁺ T cells aggregation	Induction of tumor immune escape	[312]
Immune escape	ALKBH5	Melanoma	Affects the expression of Mct4/Slc16a3 in TME to regulate the composition of tumor-infiltrating Tregs and MDSCs	Promotes melanoma escape by enhancing immunosuppressive effects	[157]
Immune escape	YTHDF1	Colon cancer	YTHDF1 induces lysosomal protease expression by recognizing its m⁶A methylation-tagged mRNA	Resulting in the inability of DCs to consistently induce tumor neoantigen production and impeding antigen-specific activation of CD8⁺ T cells	[123]
Immune escape	YTHDF2	NA	YTHDF2 exacerbates the CCR7‐induced DCs migration process and completely disables DCs by alleviating m⁶A modification‐based RNA degradation of lnc‐Dpf3	Promotes immune escape	[125]
Immune escape	FTO	Melanoma	FTO-mediated m⁶A demethylation in tumor cells enhances transcription factors c-Jun, JunB and C/EBPβ, thereby inducing hypoxia-mediated glycolytic metabolism and suppressing CD8⁺ T cell function	Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance	[129]
Immune escape	METTL3/IGF2BP3	Breast cancer	METTL3/IGF2BP3 axis upregulates m⁶A modification of PD-L1 mRNA, suppressing T cell activation in breast cancer	Promotes tumor immune escape	[130]
Immune escape	ALKBH5	NA	Deletion of ALKBH5 in T cells reduces mRNA stability and corresponding protein expression	Reduces neutrophil recruitment to the central nervous system during neuroinflammation resulting in impaired CD4⁺ T cell responses	[131]
Immune escape	METTL3	NA	Downregulation of METTL3 leads to reduced METTL3-mediated methylation of m⁶A targeting the IL-7/STAT5/SOCS pathway	Causes stagnation of T-cell development	[132]
Immune escape	YTHDF2	Lung cancer	NPM1 negatively regulates the growth and development of B and NK cells through glycolysis and YTHDF2-mediated methylation	Participates in immune infiltration of lung cancer and promotes immune tumor escape	[134]
Immune escape	METTL14	Colorectal cancer	METTL14 in TAM induces CD8⁺ T cell dysfunction	Promotes tumor progression	[149]
Immune escape	ALKBH5	Melanoma	ALKBH5 regulates the composition of tumor-infiltrating Tregs and MDSCs by affecting Mct4/Slc16a3 expression in TME	Achieves enhanced immunosuppressive effects and promotes immune escape of melanoma	[157]
Immune escape	METTL3	Melanoma	METTL3 deficiency impairs YTHDF1-mediated SPRED2 translation, in turn, enhancing NF-κB and STAT3 activation via the ERK pathway	Causes increased TAM-induced Treg infiltration into TME and supports tumor metastasis	[150]
Immune escape	WTAP	Gastric cancer	Elevated expression of WTAP affects tumor-associated T-lymphocyte infiltration	Causes poor prognosis of gastric cancer	[313]
Immune escape	METTL3	Testicular germ cell tumors	Expression of METTL3 is positively correlated with infiltration of CD8⁺ and CD4⁺ T cells	Exerts an appropriate anti-tumor immune response	[314]
Immune escape	YTHDF2/METTL3	Melanoma/ovarian cancer	YTHDF2/METTL3 maintain NK cell homeostasis and terminal maturation and promote NK cell function	Enhances anti-tumor immunity	[136, 138]
Exosomes	ALKBH5	Glioblastoma	Warburg effect promotes exosome circ_0072083 release to upregulate NANOG and ALKBH5 expression through multiple pathways	Enhances resistance to temozolomide in gliomas	[215]
Exosomes	METTL3	Lung cancer	Exosome miR-4443 regulates FSP1 m⁶A methylation-mediated ferroptosis	Promotes cisplatin resistance in lung cancer	[315]
Exosomes	METTL7A	Myeloma	Induction of m⁶A methylation in adipocyte exosomal lncRNAs to mediate myeloma drug resistance	Promotes drug resistance in myeloma and supports tumor growth	[185]
Exosomes	METTL3	Colorectal cancer	m⁶A methylation-dependent promotion of miR-181d-5p expression in cancer-associated fibroblast exosomes	Targeting NCALD inhibits 5-FU sensitivity in colorectal cancer	[176]

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