Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy

Wen Su, Mixiao Tan, Zhihang Wang, Jie Zhang, Wenping Huang, Haohao Song, Xinye Wang, Haitao Ran, Yanfeng Gao, Guangjun Nie, Hai Wang

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.

Original languageEnglish (US)
Article numbere202218128
Pages (from-to)e202218128
JournalAngewandte Chemie - International Edition
Volume62
Issue number11
DOIs
StatePublished - Mar 6 2023

Keywords

  • Cancer Therapy
  • Carbon Dots
  • Nanomedicine
  • PROTACs
  • Proteins/metabolism
  • Proteasome Endopeptidase Complex/metabolism
  • Ubiquitin-Protein Ligases/metabolism
  • B7-H1 Antigen/metabolism
  • Proteolysis
  • Humans
  • Immunotherapy
  • Neoplasms/drug therapy

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

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