연구성과 홍보

Adv Sci (Weinh). 2025 Jan;12(3):e2410806.

Title : RNA N6-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer

Authors : Dongjun Jang1, Chanwoong Hwa2,3, Seoyeon Kim2,3, Jaeik Oh4, Seungjae Shin1, Soo-Jin Lee1, Jiwon Kim1, Sang Eun Lee1, Yoojin Yang1, Dohee Kim1, Seoho Lee1, Hae Rim Jung5, Yumi Oh5, Kyunggon Kim6, Hye Seung Lee7,8, Joon-Yong An2,3,9*, Sung-Yup Cho1,4,5,8*

Affiliations :

1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.

2L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, 02841, South Korea.

3Department of Integrated Biomedical and Life Science, Korea University, Seoul, 02841, South Korea.

4Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, South Korea.

5Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.

6Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 05505, South Korea.

7Department of Pathology, Seoul National University College of Medicine, Seoul, 03080, South Korea.

8Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea.

9School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, 02841, South Korea.

DOI: 10.1002/advs.202410806

Abstract :

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 N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-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.