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

Dev Cell. 2023 May 8;58(9):760-778.e6. doi: 10.1016/j.devcel.2023.03.015. Epub 2023 Apr 12.

Abstract

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.

Keywords: JMJD8; STING; antitumor immunity; breast cancer; type I IFN signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms*
  • Endoplasmic Reticulum / metabolism
  • Female
  • Humans
  • Immune Evasion*
  • Immunity, Innate
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Signal Transduction / genetics

Substances

  • Membrane Proteins
  • JMJD8 protein, human
  • JMJD8 protein, mouse