Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy

Angew Chem Int Ed Engl. 2023 Apr 24;62(18):e202300978. doi: 10.1002/anie.202300978. Epub 2023 Mar 13.

Abstract

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

Keywords: Anticancer Agents; Immunotherapy; Protein-Protein Interaction; STING; Targeted Protein Upregulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism
  • Humans
  • Immunotherapy
  • Membrane Proteins* / metabolism
  • Neoplasms* / therapy
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Up-Regulation

Substances

  • Membrane Proteins
  • TRIM29 protein, human
  • DNA-Binding Proteins
  • Transcription Factors