Jang Dongjun, Hwa Chanwoong, Kim Seoyeon, Oh Jaeik, Shin Seungjae, Lee Soo-Jin, Kim Jiwon, Lee Sang Eun, Yang Yoojin, Kim Dohee, Lee Seoho, Jung Hae Rim, Oh Yumi, Kim Kyunggon, Lee Hye Seung, An Joon-Yong, Cho Sung-Yup
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.
L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, 02841, South Korea.
Adv Sci (Weinh). 2025 Jan;12(3):e2410806. doi: 10.1002/advs.202410806. Epub 2024 Nov 25.
Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.
免疫疗法有望成为胃癌（GC）的一种治疗方法，不过免疫检查点抑制剂（ICI）耐药性仍是一个障碍。一种耐药机制涉及干扰素-γ（IFN-γ）信号通路缺陷，其中IFN-γ与对ICI的反应性改善有关。在此，揭示了RNA N-甲基腺苷（m6A）修饰在调节IFN-γ信号通路及对ICI反应性中的作用。m6A结合蛋白YTH N-甲基腺苷RNA结合蛋白F1（YTHDF1）在GC组织中过表达，与癌症免疫抑制及较差的生存率相关。YTHDF1过表达削弱了GC细胞对IFN-γ的反应性，敲低研究表明YTHDF2和YTHDF3在IFN-γ反应性方面与YTHDF1具有冗余作用。RNA免疫沉淀测序显示YTHDFs直接靶向干扰素调节因子1（IRF1）mRNA，后者是IFN-γ信号通路的主要调节因子，导致RNA稳定性降低，进而下调IFN-γ信号通路。此外，在小鼠同基因肿瘤模型中，癌细胞中Ythdf1的缺失导致肿瘤生长减缓及肿瘤浸润淋巴细胞增加，这归因于IFN-γ信号通路的增强。总体而言，这些发现突出了YTHDFs如何通过IRF1调节影响IFN-γ信号通路来调节癌症免疫，表明它们作为癌症免疫治疗中治疗靶点的可行性。
