N6-methyladenosine (m6A) writer METTL5 represses the ferroptosis and antitumor immunity of gastric cancer

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-09-11 DOI:10.1038/s41420-024-02166-1

Xinli Li, Guoqiang Yang, Lihong Ma, Bingxi Tang, Tao Tao

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Abstract

Emerging evidence has shown that ferroptosis and antitumor immunity response of T lymphocytes play critical roles in multiple malignancies, including gastric cancer (GC). Here, the present research aims to reveal the function of novel N⁶-methyladenosine (m⁶A) methyltransferase METTL5 on GC immune microenvironment. Clinically, elevated METTL5 was negatively correlated to the prognosis of GC patients. METTL5 high-expression repressed the Fe²⁺ accumulation and ferroptosis to promote the GC immune evasion escaping from activated PBMCs’ killing effect. Mechanistically, upregulation of METTL5 promoted NRF2 mRNA stability, thereby inactivating the ferroptosis and repressing PBMCs’ cells antitumor immunity. One valuable finding is that ferroptosis inhibitor (Ferrostatin-1, Fer-1) could reduce the antitumor immunity of cocultured PBMCs. In other words, the increase of ferroptosis might contribute to the anti-tumor efficacy of immunotherapy. Further study revealed that m⁶A reader IGF2BP1 mediated the stability of NRF2 mRNA via METTL5/m⁶A/NRF2 axis. Collectively, these results demonstrate that METTL5 functions as an oncogene in GC immune microenvironment, and highlights a critical role in T lymphocytes’ antitumor immunity.

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N6-甲基腺苷（m6A）作家METTL5抑制胃癌的铁变态反应和抗肿瘤免疫力

新的证据表明，铁突变和T淋巴细胞的抗肿瘤免疫反应在包括胃癌（GC）在内的多种恶性肿瘤中发挥着关键作用。本研究旨在揭示新型 N6-甲基腺苷（m6A）甲基转移酶 METTL5 在胃癌免疫微环境中的功能。在临床上，METTL5的升高与GC患者的预后呈负相关。METTL5的高表达抑制了Fe2+的积累和铁突变，从而促进了GC免疫逃避活化的PBMCs的杀伤作用。从机理上讲，METTL5的上调促进了NRF2 mRNA的稳定性，从而使铁凋亡失活，抑制了PBMCs细胞的抗肿瘤免疫。一个有价值的发现是，铁凋亡抑制剂（Ferrostatin-1，Fer-1）可降低共培养 PBMCs 的抗肿瘤免疫力。换句话说，铁突变的增加可能有助于提高免疫疗法的抗肿瘤效果。进一步的研究发现，m6A 阅读器 IGF2BP1 通过 METTL5/m6A/NRF2 轴介导 NRF2 mRNA 的稳定性。总之，这些结果表明，METTL5 在 GC 免疫微环境中发挥着癌基因的作用，并在 T 淋巴细胞的抗肿瘤免疫中发挥着关键作用。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.