Targeted protein degradation of Wnt/β-catenin signaling pathway: an effective strategy for cancer therapy.

The Wnt/β-Catenin signaling pathway is highly conserved and initiated by a multiprotein signalosome complex. It is essential for embryonic development, organ formation, and tissue homeostasis. Abnormal Wnt signaling is found in many malignant tumors, and Wnt mutations are widely known to drive tumor initiation. Since the discovery of its oncogenic roles, numerous therapeutic agents have been developed, but none have been approved. This is attributed to the inherent structural characteristics of its core components and their role in normal tissue homeostasis. The majority of clinical drugs are occupancy-driven small molecule inhibitors, and most encounter challenges such as off-target effects and adverse toxicities. In recent years, targeted protein degradation (TPD) technology has emerged as a promising approach, offering a novel strategy for drug development targeting the Wnt/β-Catenin pathway. Utilizing this technology to degrade key proteins in the Wnt/β-Catenin pathway holds significant potential for inhibiting its oncogenic effects and restoring the cancer-immunity cycle (CI cycle). This review presents a systematic analysis of the "undruggability" of the Wnt/β-Catenin pathway and proposes potential strategies ranging from target selection to TPD application, with the aim of offering novel insights into overcoming this challenge.