Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody–drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target ‘undruggable’ Wnt signaling.
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