Department of Chemistry, The University of Chicago, Chicago, IL, USA.
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
EMBO J. 2023 Aug 1;42(15):e113126. doi: 10.15252/embj.2022113126. Epub 2023 Jun 22.
N -methyladenosine (m A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations.
N6-甲基腺苷（m6A）在信使 RNA（mRNA）中调节免疫细胞的稳态和对感染及炎症的反应。m6A 读码蛋白 YTHDF2 在这些情况下的肿瘤微环境（TME）中的功能尚未被探索。我们发现，YTHDF2 在调节性 T（Treg）细胞中的缺失会减少小鼠体内的肿瘤生长。Treg 细胞中 Ythdf2 的缺失不影响外周免疫稳态，但会导致 TME 中 Treg 细胞的凋亡增加和抑制功能受损。TME 中肿瘤坏死因子（TNF）信号的升高会促进 YTHDF2 的表达，进而通过加速降解编码 NF-κB 负调控因子的 m6A 修饰转录本来调节 NF-κB 信号。YTHDF2 对 Treg 的这种 TME 特异性调节表明 YTHDF2 是癌症免疫治疗的一个潜在靶点，其中可以靶向肿瘤内 Treg 细胞以增强抗肿瘤免疫反应，同时避免外周 Treg 细胞以最小化不必要的炎症。
