Abstract:Proteolysis targeting chimera (PROTAC) represents an effective strategy for targeted protein degradation (TPD). As a heterobifunctional molecule, PROTAC is composed of a conjugate for the protein of interest (POI), a linker, and an E3 ligase ligand. It induces ubiquitin-proteasome system (UPS)-mediated protein degradation by hijacking the cellular UPS, thereby removing specific oncogenic proteins from cells. Till now, an increasing number of PROTACs targeting gastrointestinal cancer have been successfully developed, with many POIs validated as effective targets for clinical drugs. This article will elucidate the working mechanism of PROTACs, their research progress, and their applications in the study of gastrointestinal cancer. Furthermore, it will explore the advantages and potential challenges of PROTACs in cancer treatment, as well as their prospects in future antitumor therapies.