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

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.

Automated summary

Proteolysis targeting chimeras (PROTACs) technology is a promising method for degrading disease-associated proteins. In this study, carbon-dot (CD)-based PROTACs (CDTACs) were developed to degrade membrane proteins via the ubiquitin-proteasome system. CDTACs demonstrated efficient degradation of programmed cell death ligand 1 (PD-L1) and activation of the stimulator of interferon genes (STING) pathway, leading to the inhibition of tumor growth. CDTACs offer advantages such as targeted tumor accumulation, immune system activation, and in vivo detection compared to small-molecule-based PROTACs.