A20 Inhibits IFN-γ Signaling in Hepatocellular Carcinoma Cells by Binding to STAT1, Compromising Anti-Tumor Immunity.

Authors

Yanlei Dong, Jing Yi, Ruoxuan Yang, Yingyue Wang, Zelong Ma, Hong Yuan, Meichen Song, Ying Xiao, Chun Guo, Jianing Wang, Xiaoyan Wang, Faliang Zhu, Lining Zhang, Yuchen Fan, Yongyu Shi

Published in

Cancer science. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

Immune checkpoint blockade (ICB) has demonstrated efficacy in clinical cancer therapy; however, a significant proportion of cancer patients do not respond to ICB. One contributing factor to this lack of response is the impairment of IFN-γ signaling within cancer cells. A20 acts as a negative regulator of IFN-γ signaling. Our study aimed to investigate the mechanism by which A20 exerts its negative regulatory effect on IFN-γ signaling in hepatocellular carcinoma (HCC) cells. Bioinformatic analysis revealed that A20 expression in HCC cell lines is inversely associated with the activation of IFN-γ signaling. Functional loss and gain experiments demonstrated that A20 inhibits IFN-γ signaling in HCC cells. The interaction between A20 and STAT1 was assessed using Co-Immunoprecipitation (Co-IP) assays and bimolecular fluorescence complementation (BioFC) assays. Our results also indicated that A20 suppresses the expression of downstream molecules involved in IFN-γ signaling, such as CXCL9, CXCL10, and HLA-ABC, in HCC cells. Additionally, enforced expression of A20 in HCC cells inhibited anti-tumor immunity in a mouse model of HCC. Bioinformatic analysis suggests that A20 may negatively regulate IFN-γ signaling in HCC cells from human HCC cohorts. Collectively, our study uncovers a novel mechanism whereby A20 inhibits IFN-γ signaling in HCC cells through direct binding with STAT1. These findings enhance our understanding of the regulatory mechanisms of IFN-γ signaling in cancer cells and provide insights for designing strategies to enhance the effectiveness of ICB therapy.

PMID:
42844863
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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