Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), remains one of the deadliest malignancies worldwide, with a five-year survival rate lingering below 12 % [1]. Characterized by late diagnosis, rapid progression, and early metastasis, more than 80 % of patients are diagnosed at an advanced or unresectable stage [2]. Moreover, the intrinsic and acquired resistance to conventional chemotherapies, such as gemcitabine or FOLFIRINOX, has severely hampered therapeutic efficacy and long-term patient survival [3]. Recent advances in cancer genomics and molecular biology have led to the identification of several key oncogenic drivers and regulators in pancreatic cancer, including KRAS mutations, MYC, BRD4, BCL-XL, FOXM1, and STAT3. However, these proteins typically lack well-defined ligand-binding pockets, rendering them “undruggable” by traditional small-molecule inhibitors [4]. This represents a major obstacle in developing targeted therapies for pancreatic cancer, highlighting an urgent need for innovative therapeutic strategies capable of modulating such elusive targets.

Proteolysis-targeting chimeras (PROTACs), a cutting-edge modality in the field of targeted protein degradation (TPD), have emerged as a powerful approach to overcome the limitations of conventional drug development. Unlike occupancy-driven inhibitors that require continuous binding to suppress protein function, PROTACs operate via an event-driven mechanism [5,6]. They recruit an E3 ubiquitin ligase to the protein of interest (POI), promoting its ubiquitination and subsequent degradation by the 26S proteasome [7]. This approach not only expands the druggable proteome to include non-enzymatic and scaffold proteins, but also allows for catalytic and substoichiometric mode of action, which can enhance potency and reduce dosing requirements [8,9].

Encouragingly, several PROTAC-based therapeutics have entered clinical trials for various cancers and have shown promising efficacy, particularly in hematologic malignancies and prostate cancer [[10], [11], [12]]. Although the application of PROTACs in pancreatic cancer is still in its early stages, their mechanism aligns well with the unique molecular landscape of PDAC. PROTACs offer a compelling strategy to directly eliminate oncogenic drivers, epigenetic regulators, anti-apoptotic proteins, and transcription factors (TFs) that are otherwise challenging to inhibit [13,14].

In this review, we provide a comprehensive overview of the design principles and functional components of PROTACs, summarize recent progress in targeting key proteins involved in pancreatic cancer using this technology, and discuss the challenges and strategies related to PROTAC development. This article aims to inform future research and therapeutic innovation in the field of pancreatic cancer by highlighting the promise and limitations of PROTAC-based therapies.