RNA methyltransferase FTSJ3 regulates the type I interferon pathway to promote hepatocellular carcinoma immune evasion.

Abstract

Immunotherapies such as immune checkpoint blockade have achieved remarkable success in treating cancer. Unfortunately, response rates have been limited in multiple cancers including hepatocellular carcinoma (HCC). The critical function of epigenetics in tumor immune evasion and anti-tumor immunity supports harnessing epigenetic regulators as a potential strategy to enhance the efficacy of immunotherapy. Here, we discovered a tumor-promoting function of FTSJ3, an RNA 2'-O-methyltransferase, in HCC by suppressing anti-tumor immune responses. FTSJ3 was upregulated in hepatocellular carcinoma, and high FTSJ3 expression correlated with reduced patient survival. Deletion of FTSJ3 blocked HCC growth and induced robust anti-tumor immune responses. Mechanistically, FTSJ3 suppressed double-stranded RNA (dsRNA)-induced IFNβ signaling in a 2'-O-methyltransferase manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, indicating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. Furthermore, FTSJ3 deletion significantly enhanced the efficacy of PD-1 immune checkpoint blockade. The combination of FTSJ3 deficiency and anti-PD-1 antibody treatment effectively eradicated tumors and increased the survival time. In conclusion, this study reveals an epigenetic mechanism of tumor immune evasion and, importantly, suggests FTSJ3-targeting therapies as potential approach to overcome immunotherapy resistance in HCC patients.

• Authors: Qiuyu Zhuang, Zhiguo Dai, Xuechun Xu, Shaoyi Bai, Yindan Zhang, Youshi Zheng, Xiaohua Xing, En Hu, Yingchao Wang, Wuhua Guo, Bixing Zhao, Yongyi Zeng, Xiaolong Liu
• Journal: Cancer research (Cancer Res) (Nov 14 2023) ISSN: 1538-7445 [Electronic] United States
• PMID: 37963197 (Publication Type: Journal Article)