Targeted protein degradation in pancreatic cancer: advances and challenges of PROTAC-based therapeutics

Pancreatic cancer remains one of the deadliest malignancies, with limited therapeutic options and a dismal prognosis. Traditional treatment modalities, including chemotherapy and molecular targeted therapies, often face challenges such as drug resistance, limited targetability, and systemic toxicity. The emergence of proteolysis-targeting chimeras (PROTACs) has opened a new frontier in targeted protein degradation, offering a promising approach to overcome these limitations by hijacking the ubiquitin-proteasome system to selectively degrade disease-related proteins. This review provides a comprehensive overview of the design principles and molecular components of PROTACs, including POI ligands, E3 ligase ligands, and linker strategies. We further highlight recent progress in the application of PROTACs in pancreatic cancer therapy, focusing on their ability to target oncogenic kinases, epigenetic regulators, antiapoptotic proteins, metabolic regulators, and transcription factors. Despite significant advances, the clinical translation of PROTACs faces multiple challenges, including poor cell permeability, off-target effects, tissue toxicity, and acquired resistance. Finally, we discuss future perspectives on rational design, tissue-specific delivery systems, and combination strategies to fully realize the therapeutic potential of PROTACs in pancreatic cancer treatment.