Progress of N6-methyladenosine modification in regulating the tumor immune microenvironment

doi:10.12092/j.issn.1009-2501.2026.04.014

Abstract

Abstract:

N6-methyladenosine (m⁶A), as the most prevalent and abundant RNA methylation modification, regulates RNA transcript stabilization, translation efficiency and pre-mRNA splicing and influences several biological processes and plays multiple roles in cancers. The tumor immune microenvironment consists of a variety of immune cells, cytokines, extracellular matrix and other tissue-resident cells that influence tumor growth, metastasis, and drug response. Based on the role of m⁶A modification in the expression of various immune-related genes, this review provides a comprehensive understanding of how m⁶A function in tumor immunity by directly regulating different immune cells as well as indirectly modulating the secretion of immune-related factors.

Key words: N6-methyladenosine (m⁶A), tumor immune microenvironment, immune cells, cytokines, immunotherapy

CLC Number:

Yu ZHANG, Wenbin XU, Yueqin WANG. Progress of N6-methyladenosine modification in regulating the tumor immune microenvironment[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(4): 543-550.

Figures/Tables 1

References 54

1	Bejarano L, Jordão MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment[J]. Cancer Discov, 2021, 11 (4): 933- 959. doi: 10.1158/2159-8290.CD-20-1808
2	Park J, Hsueh PC, Li Z, et al. Microenvironment-driven metabolic adaptations guiding CD8⁺ T cell anti-tumor immunity[J]. Immunity, 2023, 56 (1): 32- 42. doi: 10.1016/j.immuni.2022.12.008
3	Liu Q, Gregory RI. RNAmod: an integrated system for the annotation of mRNA modifications[J]. Nucleic Acids Res, 2019, 47 (W1): W548- W555. doi: 10.1093/nar/gkz479
4	吕楠, 吕志峰. m⁶A 修饰在慢性疼痛中的研究进展[J]. 中国疼痛医学杂志, 2023, 29 (7): 528- 534. doi: 10.3969/j.issn.1006-9852.2023.07.008
5	Wang X, Feng J, Xue Y, et al. Structural basis of N (6)-adenosine methylation by the METTL3-METTL14 complex[J]. Nature, 2016, 534 (7608): 575- 578.
6	Schöller E, Weichmann F, Treiber T, et al. Interactions, localization, and phosphorylation of the m⁶A generating METTL3–METTL14–WTAP complex[J]. RNA, 2018, 24 (4): 499- 512. doi: 10.1261/rna.064063.117
7	Coker H, Wei G, Moindrot B, et al. The role of the Xist 5' m6A region and RBM15 in X chromosome inactivation[J]. Wellcome Open Res, 2020, 5, 31. doi: 10.12688/wellcomeopenres.15711.1
8	Mauer J, Sindelar M, Despic V, et al. FTO controls reversible m6Am RNA methylation during snRNA biogenesis[J]. Nat Chem Biol, 2019, 15 (4): 340- 347. doi: 10.1038/s41589-019-0231-8
9	温媛媛, 黄凯玥, 史会连, 等. m⁶A 甲基化修饰的研究进展[J]. 生命的化学, 2022, 42 (2): 275- 282.
10	Weng H, Huang F, Yu Z, et al. The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia [J]. Cancer Cell, 2022, 40 (12): 1566-1582. e10.
11	Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer[J]. Biomed Pharmacother, 2019, 112, 108613. doi: 10.1016/j.biopha.2019.108613
12	施经斌, 熊阳. 肿瘤微环境与乳腺癌细胞互作导致肿瘤转移的研究进展[J]. 中国临床药理学与治疗学, 2022, 27 (5): 562- 574. doi: 10.12092/j.issn.1009-2501.2022.05.010
13	Kong F, Wang K, Wang L. Systematic analysis of the expression profile and prognostic significance of m6A regulators and PD-L1 in hepatocellular carcinoma[J]. Discover Oncol, 2022, 13 (1): 131. doi: 10.1007/s12672-022-00595-x
14	Xi Q, Yang G, He X, et al. M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages[J]. Adv Sci (Weinh), 2024, 11 (34): e2400695. doi: 10.1002/advs.202400695
15	Xu W, Tao M, Liu Y, et al. METTL3-mediated SMPDL3A promotes cell growth, metastasis and immune process of hepatocellular carcinoma by regulating LRPPRC[J]. Cell Signal, 2025, 127, 111543. doi: 10.1016/j.cellsig.2024.111543
16	Yu F, Feng Y, Wang Q, et al. N6-methyladenosine (m6A) Writer WTAP potentiates hepatocellular carcinoma immune evasion and aerobic glycolysis[J]. Cell Biochem Biophys, 2024, 82 (3): 2321- 2331. doi: 10.1007/s12013-024-01342-5
17	Chen A, Zhang VX, Zhang Q, et al. Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma[J]. Gut, 2024, 74 (1): 90- 102. doi: 10.1136/gutjnl-2024-331903
18	Tsuchiya K, Yoshimura K, Inoue Y, et al. YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer[J]. Oncoimmunology, 2021, 10 (1): 1962656. doi: 10.1080/2162402X.2021.1962656
19	Liu Z, Wang T, She Y, et al. N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer[J]. Mol Cancer, 2021, 20 (1): 105. doi: 10.1186/s12943-021-01398-4
20	Wang X, Chen C, Sun H, et al. m6A mRNA modification potentiates Th17 functions to inflame autoimmunity[J]. Sci China Life Sci, 2023, 66 (10): 1921- 1934. doi: 10.1007/s11427-022-2323-4
21	Zhong J, Liu Z, Cai C, et al. m⁶A modification patterns and tumor immune landscape in clear cell renal carcinoma[J]. J Immunother Cancer, 2021, 9 (2): e001646. doi: 10.1136/jitc-2020-001646
22	Tong J, Cao G, Zhang T, et al. m6A mRNA methylation sustains Treg suppressive functions[J]. Cell Res, 2018, 28 (2): 253- 256. doi: 10.1038/cr.2018.7
23	Song H, Song J, Cheng M, et al. METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells[J]. Nat Commun, 2021, 12 (1): 5522. doi: 10.1038/s41467-021-25803-0
24	Wang J, Luo J, Wu X, et al. WTAP enhances the instability of SYTL1 mRNA caused by YTHDF2 in bladder cancer[J]. Histol Histopathol, 2024, 39 (5): 633- 646.
25	Ma S, Yan J, Barr T, et al. The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity[J]. J Exp Med, 2021, 218 (8): e20210279. doi: 10.1084/jem.20210279
26	Wang H, Hu X, Huang M, et al. Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation[J]. Nat Commun, 2019, 10 (1): 1898. doi: 10.1038/s41467-019-09903-6
27	Han D, Liu J, Chen C, et al. Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells[J]. Nature, 2019, 566 (7743): 270- 274. doi: 10.1038/s41586-019-0916-x
28	Wen C, Wang L, Piffkó A, et al. YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production[J]. J Clin Invest, 2024, 134 (23): e181612. doi: 10.1172/JCI181612
29	Bai X, Wong CC, Pan Y, et al. Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells[J]. J Immunother Cancer, 2022, 10 (2): e003663. doi: 10.1136/jitc-2021-003663
30	Liu Y, Liu Z, Tang H, et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA[J]. Am J Physiol Cell Physiol, 2019, 317 (4): C762- C775. doi: 10.1152/ajpcell.00212.2019
31	Tong J, Wang X, Liu Y, et al. Pooled CRISPR screening identifies m6A as a positive regulator of macrophage activation[J]. Sci Adv, 2021, 7 (18): eabd4742. doi: 10.1126/sciadv.abd4742
32	Yin H, Zhang X, Yang P, et al. RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming[J]. Nat Commun, 2021, 12 (1): 1394. doi: 10.1038/s41467-021-21514-8
33	Dong L, Chen C, Zhang Y, et al. The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth [J]. Cancer Cell, 2021, 39 (7): 945-957. e10.
34	Wei H, Li W, Yang M, et al. METTL3/16-mediated m6A modification of ZNNT1 promotes hepatocellular carcinoma progression by activating ZNNT1/osteopontin/S100A9 positive feedback loop-mediated crosstalk between macrophages and tumour cells[J]. Clin Immunol, 2024, 261, 109924. doi: 10.1016/j.clim.2024.109924
35	Ma S, Sun B, Duan S, et al. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells[J]. Nat Immunol, 2023, 24 (2): 255- 266. doi: 10.1038/s41590-022-01398-6
36	Ye Y, Wang M, Wang G, et al. lncRNA miR4458HG modulates hepatocellular carcinoma progression by activating m6A-dependent glycolysis and promoting the polarization of tumor-associated macrophages[J]. Cell Mol Life Sci, 2023, 80 (4): 99. doi: 10.1007/s00018-023-04741-8
37	Chen H, Pan Y, Zhou Q, et al. METTL3 inhibits antitumor immunity by targeting m6A-BHLHE41-CXCL1/CXCR2 axis to promote colorectal cancer[J]. Gastroenterology, 2022, 163 (4): 891- 907. doi: 10.1053/j.gastro.2022.06.024
38	Ni HH, Zhang L, Huang H, et al. Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer[J]. J Transl Med, 2020, 18 (1): 393. doi: 10.1186/s12967-020-02553-z
39	Wang J, Ling D, Shi L, et al. METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells[J]. Cell Biosci, 2023, 13 (1): 202. doi: 10.1186/s13578-023-01149-6
40	Feng L, Li M, Ma J, et al. ALKBH5 regulates arginase 1 expression in MDSCs and their immunosuppressive activity in tumor-bearing host[J]. Noncoding RNA Res, 2024, 9 (3): 913- 920. doi: 10.1016/j.ncrna.2024.03.003
41	Wang L, Dou X, Chen S, et al. YTHDF2 inhibition potentiates radiotherapy antitumor efficacy [J]. Cancer Cell, 2023, 41 (7): 1294-1308. e8.
42	Wang L, Hui H, Agrawal K, et al. m6A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy[J]. EMBO J, 2020, 39 (20): e104514. doi: 10.15252/embj.2020104514
43	Mu X, Wu K, Zhu Y, et al. Intra-arterial infusion chemotherapy utilizing cisplatin inhibits bladder cancer by decreasing the fibrocytic myeloid-derived suppressor cells in an m6A-dependent manner[J]. Mol Immunol, 2021, 137, 28- 40. doi: 10.1016/j.molimm.2021.06.012
44	Zeng X, Chen K, Li L, et al. Epigenetic activation of RBM15 promotes clear cell renal cell carcinoma growth, metastasis and macrophage infiltration by regulating the m6A modification of CXCL11[J]. Free Radic Biol Med, 2022, 184, 135- 147. doi: 10.1016/j.freeradbiomed.2022.03.031
45	Dong F, Qin X, Wang B, et al. ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment[J]. Cancer Res, 2021, 81 (23): 5876- 5888. doi: 10.1158/0008-5472.CAN-21-1456
46	You Y, Wen D, Zeng L, et al. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression[J]. Int J Biol Sci, 2022, 18 (13): 5001- 5018. doi: 10.7150/ijbs.70149
47	Jin S, Li M, Chang H, et al. The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma[J]. Mol Cancer, 2022, 21 (1): 97. doi: 10.1186/s12943-022-01572-2
48	Wang YF, Zhang WL, Li ZX, et al. METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression[J]. Signal Transduct Target Ther, 2024, 9 (1): 91. doi: 10.1038/s41392-024-01797-1
49	Zheng H, Zheng WJ, Wang ZG, et al. Decreased expression of programmed death ligand-L1 by seven in absentia homolog 2 in cholangiocarcinoma enhances T-cell-mediated antitumor activity[J]. Front Immunol, 2022, 13, 845193. doi: 10.3389/fimmu.2022.845193
50	Liu Y, Liang G, Xu H, et al. Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance [J]. Cell Metab, 2021, 33 (6): 1221-1233. e11.
51	Wang L, Zhu L, Liang C, et al. Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts antitumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis[J]. J Hepatol, 2023, 79 (5): 1185- 1200. doi: 10.1016/j.jhep.2023.06.021
52	Zhang H, Luo X, Yang W, et al. YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity[J]. Nat Commun, 2024, 15 (1): 9559. doi: 10.1038/s41467-024-53997-6
53	Liu J, Zhang X, Chen K, et al. CCR7 Chemokine receptor-inducible lnc-dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis [J]. Immunity, 2019, 50 (3): 600-615. e15.
54	Li Y, Xia L, Tan K, et al. N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2[J]. Nat Genet, 2020, 52 (9): 870- 877. doi: 10.1038/s41588-020-0677-3

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