METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Song, Hao; Song, Jiuzhou; Cheng, Ming; Zheng, Meijuan; Wang, Tian; Tian, Sha; Flavell, Richard A.; Zhu, Shu; Li, Hua Bing; Chen, Ding; Wei, Haiming; Sun, Rui; Peng, Hui; Tian, Zhigang

doi:10.1038/s41467-021-25803-0

Cited by 103 publications

(62 citation statements)

References 62 publications

(64 reference statements)

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“…Subsequently, a related study unveiled a critical role of METTL3-mediated m 6 A methylation in the homeostasis and anti-tumor immunity of NK cells. In that study, mice with conditional Mettl3 depletion in NK cells showed aggravated tumor progression and shortened survival, accompanied by suppressed infiltration and impaired tumor immunosurveillance functions of NK cells in the TME 52 . Overall, these observations have elucidated the role of m 6 A modification in the anti-tumor immunity of NK cells, highlighting new biological roles of m 6 A modification in tumor immune regulation in NK cells.…”

Section: A Modification In Nk Cellsmentioning

confidence: 83%

N6-methyladenosine (m6A) RNA modification in tumor immunity

Zheng¹,

Han²,

Lin³

2022

Cancer Biol Med

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Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion. Importantly, recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition. N6-methyladenosine (m6A) modification, the most prevalent epigenetic modification of mammalian mRNAs, has essential functions in regulating the processing and metabolism of its targeted RNAs, and therefore affects various biological processes including tumorigenesis and progression. Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m6A modification in the regulation of tumor immunity. In this review, we summarize recent research progress in the potential roles of m6A modification in tumor immunoregulation, with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways. Furthermore, we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape, and we discuss the prognostic value and therapeutic efficacy of m6A regulators in a variety of cancer types.

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Section: A Modification In Nk Cellsmentioning

confidence: 83%

N6-methyladenosine (m6A) RNA modification in tumor immunity

Zheng¹,

Han²,

Lin³

2022

Cancer Biol Med

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“…Subsequently, Chen et al observed that mRNA levels of the m 6 A writer METTL3 were decreased in tumor-infiltrating NK cells of certain cancer patients. Using mouse models, they also showed that deleting METTL3 reduced NK cell hyporesponsiveness to IL-15, promoted tumor progression and metastasis by targeting SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) [ 34 ]. As both the m 6 A writer METTL3 and the reader YTHDF2 positively regulate the anti-tumor immunity of NK cells, METTL3- and YTHDF2-mediated m 6 A methylation might be important regulators of anti-tumor immunity and homeostasis of NK cells (Fig.…”

Section: Role Of the M 6 A Modification In Immune ...mentioning

confidence: 99%

“…As both the m 6 A writer METTL3 and the reader YTHDF2 positively regulate the anti-tumor immunity of NK cells, METTL3- and YTHDF2-mediated m 6 A methylation might be important regulators of anti-tumor immunity and homeostasis of NK cells (Fig. 2 A) [ 34 ]. However, the effector functions and regulatory mechanisms of other m 6 A regulators on NK cells remain to be determined.…”

Section: Role Of the M 6 A Modification In Immune ...mentioning

confidence: 99%

“…Another reason is the complexity of the TME of solid tumors, which is tightly associated with the clinical outcome of cancer patients [ 123 ]. In a couple of solid tumors, the other group and we have uncovered beneficial roles for regulators, such as METTL3 and YTHDF2, in the immune response to tumor cells by NK cells [ 33 , 34 ]. Therefore, m 6 A inhibitors that target tumor cells may impair the anti-tumor immune response.…”

Section: Strategies and Challenges Of Targeting M 6 ...mentioning

confidence: 99%

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Targeting the RNA m6A modification for cancer immunotherapy

Deng

et al. 2022

Mol Cancer

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N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

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“…The genetic perturbation of the m6A machinery (writer, reader, and eraser genes) in different experimental models affects a striking variety of molecular processes including, but not restricted to: adipogenesis [ 59 ], spermatogenesis [ 15 , 34 ], oocyte maturation [ 35 , 60 ], neurodevelopment [ 61 , 62 , 63 ], pluripotency [ 21 , 54 , 55 ], circadian rhythm regulation [ 64 ], senescence [ 65 ], multiple cancerous traits [ 52 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ], and antitumor immunity [ 73 , 74 ].…”

Section: Rna Modificationsmentioning

confidence: 99%

Driving Chromatin Organisation through N6-methyladenosine Modification of RNA: What Do We Know and What Lies Ahead?

Selmi

Lanzuolo

2022

Genes

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In recent years, there has been an increase in research efforts surrounding RNA modification thanks to key breakthroughs in NGS-based whole transcriptome mapping methods. More than 100 modifications have been reported in RNAs, and some have been mapped at single-nucleotide resolution in the mammalian transcriptome. This has opened new research avenues in fields such as neurobiology, developmental biology, and oncology, among others. To date, we know that the RNA modification machinery finely tunes many diverse mechanisms involved in RNA processing and translation to regulate gene expression. However, it appears obvious to the research community that we have only just begun the process of understanding the several functions of the dynamic web of RNA modification, or the “epitranscriptome”. To expand the data generated so far, recently published studies revealed a dual role for N6-methyladenosine (m6A), the most abundant mRNA modification, in driving both chromatin dynamics and transcriptional output. These studies showed that the m6A-modified, chromatin-associated RNAs could act as molecular docks, recruiting histone modification proteins and thus contributing to the regulation of local chromatin structure. Here, we review these latest exciting findings and outline outstanding research questions whose answers will help to elucidate the biological relevance of the m6A modification of chromatin-associated RNAs in mammalian cells.

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METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Cited by 103 publications

References 62 publications

N6-methyladenosine (m6A) RNA modification in tumor immunity

N6-methyladenosine (m6A) RNA modification in tumor immunity

Targeting the RNA m6A modification for cancer immunotherapy

Driving Chromatin Organisation through N6-methyladenosine Modification of RNA: What Do We Know and What Lies Ahead?

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