WNT signaling in cancer: molecular mechanisms and potential therapies

The WNT signaling pathway, a fundamental molecular network regulating cell proliferation, differentiation, and stemness, plays a critical role in tumorigenesis, cancer progression, and therapeutic resistance. Given its crucial regulatory roles in tumors, WNT signaling pathway has been identified as effective targets for cancer treatment. However, the current clinical efficacy of WNT signaling pathway-targeted anti-tumor therapies remains suboptimal. Based on research investigating the role of WNT signaling pathway in cancer, we systematically discuss the molecular mechanisms of WNT signaling in cancer (including both canonical and non-canonical signaling pathways), the role of WNT signaling in different cancer types, highlighting distinct potential therapeutic approaches targeting WNT signaling. We also comprehensively review innovative strategies targeting WNT signaling, including Porcupine (PORCN) inhibitors, Tankyrase (TNKS) inhibitor, Frizzled (FZD)-targeted monoclonal antibodies, β-catenin/TCF transcriptional complex inhibitors, and natural bioactive compounds and drug repositioning etc., critically evaluating their preclinical efficacy and limitations. We emphasize the need for and challenges in developing WNT-targeted therapies including refining the specificity of WNT signaling pathway-targeted therapies, developing biomarkers for patient selection, and exploring synergies between WNT inhibitors and other therapeutic modalities such as immune checkpoint blockers. These advances aim to enable personalized precision therapy and revolutionize cancer treatment paradigms in the future.