Abstract 6047: YTHDF proteins modulate gastric cancer immunity by regulating the IFN-γ response through the m6A-dependent degradation of IRF1

Abstract N6-methyladenosine (m6A) RNA methylation is one of the most abundant post-transcriptional modifications in eukaryotic messenger RNAs and plays crucial roles in carcinogenesis and immune responses. YTHDF proteins including YTHDF1, 2, and 3 are ‘reader’ proteins of m6A methylated RNAs and have individual role. A recent report suggests that YTHDFs act redundantly to promote RNA decay. In this study, we found that YTHDF1 was overexpressed in gastric cancer (GC) tissues and correlating with the suppression of cancer immunity, particularly the responsiveness to interferon-gamma (IFN-γ). Overexpression of YTHDF1 reduced the responsiveness to IFN-γ in GC cells, while knockdown studies showed that YTHDF2 and YTHDF3 redundantly affect IFN-γ responsiveness alongside YTHDF1. Analysis of RNA immunoprecipitation (RIP)-sequencing data revealed that IRF1 mRNA, key regulator of IFN-γ signaling, is a direct target of YTHDFs and is degraded in an m6A-dependent manner. Likewise, downregulation of METTL3, which is a major component of m6A methyltransferase complex, using small interfering RNA or catalytic inhibitor increase IRF1 levels and IFN-γ responsiveness. Furthermore, depletion of Ythdf1 reduced tumor growth and increased immune cell infiltration into the tumor, dependent on IFN-γ signaling in mouse syngeneic tumor models. Collectively, our study suggests that YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation. Citation Format: Dongjun Jang, Sung-Yup Cho. YTHDF proteins modulate gastric cancer immunity by regulating the IFN-γ response through the m6A-dependent degradation of IRF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6047.