ER-localized JmjC domain-containing protein JMJD8 targets STING to promote immune evasion and tumor growth in breast cancer

• DOI: 10.1016/j.devcel.2023.03.015
• Publication Date: 2023-04-12T14:34:06Z
• Authors: Jia Yi; Lei Wang; Jiao Du; Mingyue Wang; Haifeng Shen; Zhiying Liu; Yao Qin; Jing Liu; Guosheng Hu; Rongquan Xiao; Jiancheng Ding; Xiaoyan Chen; Hongjiao Wang; Haihua Huang; Gaoliang Ouyang; Wen Liu
• Keywords: Mice; Animals; Humans; Membrane Proteins; Female; Breast Neoplasms; Endoplasmic Reticulum; Immunity, Innate; 3. Good health; Immune Evasion; Signal Transduction

The STING-mediated type I interferon (IFN) signaling pathway has been shown to play critical roles in antitumor immunity. Here, we demonstrate that an endoplasmic reticulum (ER)-localized JmjC domain-containing protein, JMJD8, inhibits STING-induced type I IFN responses to promote immune evasion and breast tumorigenesis. Mechanistically, JMJD8 competes with TBK1 for binding with STING, blocking STING-TBK1 complex formation and restricting type I IFN and IFN-stimulated gene (ISG) expression as well as immune cell infiltration. JMJD8 knockdown improves the efficacy of chemotherapy and immune checkpoint therapy in treating both human and mouse breast cancer cell-derived implanted tumors. The clinical relevance is highlighted in that JMJD8 is highly expressed in human breast tumor samples, and its expression is inversely correlated with that of type I IFN and ISGs as well as immune cell infiltration. Overall, our study found that JMJD8 regulates type I IFN responses, and targeting JMJD8 triggers antitumor immunity.