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Review
. 2022 Jul 6;15(1):84.
doi: 10.1186/s13045-022-01304-5.

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

Fusheng Zhang #  1 , Haiyang Liu #  1 , Meiqi Duan  1 , Guang Wang  1 , Zhenghou Zhang  1 , Yutian Wang  1 , Yiping Qian  1 , Zhi Yang  2 , Xiaofeng Jiang  3
Affiliations
Review

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

Fusheng Zhang et al. J Hematol Oncol. .

Abstract

The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, and immunosuppression. One of the most common RNA modifications, N6-methyladenosine (m6A) methylation, is widely involved in the regulation of physiological and pathological processes, including tumor development. Compelling evidence indicates that m6A methylation regulates transcription and protein expression through shearing, export, translation, and processing, thereby participating in the dynamic evolution of TME. Specifically, m6A methylation-mediated adaptation to hypoxia, metabolic dysregulation, and phenotypic shift of immune cells synergistically promote the formation of an immunosuppressive TME that supports tumor proliferation and metastasis. In this review, we have focused on the involvement of m6A methylation in the dynamic evolution of tumor-adaptive TME and described the detailed mechanisms linking m6A methylation to change in tumor cell biological functions. In view of the collective data, we advocate treating TME as a complete ecosystem in which components crosstalk with each other to synergistically achieve tumor adaptive changes. Finally, we describe the potential utility of m6A methylation-targeted therapies and tumor immunotherapy in clinical applications and the challenges faced, with the aim of advancing m6A methylation research.

Keywords: Exosomes; Hypoxia; Immune escape; Tumor biological functions; Tumor combination therapy; Tumor metabolism.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Effects of m6A modification on immune cells in hypoxia and metabolic TME. The different colored lines represent interactions of m6A modifications in immune cells through the respective pathways
Fig. 2
Fig. 2
Effects of m6A modifications in hypoxia and metabolic TME on tumor biological functions. The different colored lines represent the interactions of m6A modifications in tumor biological functions through the respective pathways
Fig. 3
Fig. 3
m6A methylation promotes immunosuppressive TME properties and supports tumor proliferation through pathways involving hypoxia, metabolic dysregulation, tumor exosomes and immune cells. HIF influences tumor cells under hypoxic conditions through m6A methylation modifications. Tumor cells in hypoxia accelerate the release of exosomes, contributing to the formation of immunosuppressive TME. m6A-mediated metabolic dysregulation generates an acidic environment that further supports tumor growth and exacerbates tumor hypoxia. A number of metabolites support immunosuppressive characteristics. In hypoxic conditions, tumors undergo metabolic reprogramming mediated by a HIF-induced positive feedback loop to further exacerbate metabolic dysregulation. Additionally, m6A methylation directly regulates immune cells to promote the progressive establishment of immunosuppressive TME
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References

    1. Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer. 2020;19:88. doi: 10.1186/s12943-020-01204-7. - DOI - PMC - PubMed
    1. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–206. doi: 10.1038/nature11112. - DOI - PubMed
    1. Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–189. doi: 10.1038/cr.2014.3. - DOI - PMC - PubMed
    1. Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell. 2016;63:306–317. doi: 10.1016/j.molcel.2016.05.041. - DOI - PMC - PubMed
    1. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, Sun HY, Li A, Ping XL, Lai WY, et al. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507–519. doi: 10.1016/j.molcel.2016.01.012. - DOI - PubMed

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