Transmembrane proteins, which comprise approximately one third of the human proteome, have crucial roles in signal transduction, metabolic regulation and disease development. However, effective strategies for their targeted degradation have remained limited. Current proteolysis-targeting chimera (PROTAC) technologies primarily rely on cytoplasmic E3 ubiquitin ligases (such as the protein cereblon) and are therefore restricted to intracellular proteins, leaving membrane and secretory proteins largely inaccessible to existing approaches. Developing degradation strategies beyond conventional PROTACs is therefore of conceptual and practical importance.
Using PDL1, a key immunotherapy target, as a model, we found that ERADECs markedly reduce its protein levels in a SYVN1- and ERAD-dependent manner. In a humanized mouse xenograft model, ERADECs showed clear anti-tumour activity, outperforming antibody-based blockade of PDL1. Further experiments suggested that the system enables efficient and selective degradation at low concentrations and can be extended to diverse transmembrane proteins.
