Anti‐Neoplastic Gallium‐Based PROTAC for PDI Degradation Triggers Autophagy and Immunogenic Cell Death

Protein disulfide isomerase (PDI), a family of thiol-disulfide oxidoreductases, is one of the most abundant soluble proteins in the endoplasmic reticulum (ER) and is responsible for protein folding. Increasing evidence suggests that PDI is overexpressed in multiple types of cancer, positioning it as a promising target for tumor therapy. We have designed and synthesized a series of gallium complex-based proteolysis targeting chimeras (PROTACs), which exhibited effective targeting and degradation of PDI in vitro. After analyzing the relationship between structure and function, we have identified M-2 as the compound that most efficiently degrades PDI. Our research shows that M-2-induced degradation of PDI can trigger the unfolded protein response, leading to cell autophagy and initiating immunogenic cell death (ICD), as demonstrated in mouse models. This study suggests a potential opportunity for combining PDI targeting and immunotherapy.