Abstract: The Wingless/Integrated (Wnt) signaling pathway governs embryogenesis, stem-cell renewal, and tissue repair; its dysregulation is a pivotal oncogenic driver. This review integrates recent multi-omic and translational studies to delineate how canonical and non-canonical Wnt cascades initiate, maintain, and disseminate tumors across diverse organs. We summarize mutational hotspots, including APC, CTNNB1, RNF43, and ZNRF3, which trigger ligand-independent β- catenin stabilization, and contrast these with ligand-driven circuits within the tumor microenvironment (TME) that amplify inter- and intratumoral heterogeneity. Tumor-specific expression profiles reveal the biphasic role of Wnt-4 in clear-cell renal carcinoma, β-catenin-mediated aggressiveness in triple-negative breast cancer, and LEF1-dependent transcriptional programs in pediatric hepatoblastoma and medulloblastoma. Crosstalk with TGF-β and Notch pathways, as well as the epithelial- mesenchymal transition (EMT) program, sustains cancer stem-cell traits, fuels metastasis, and underpins resistance to chemotherapy, radiotherapy, and immunotherapy. Mechanistically, Wnt signaling up-regulates multidrug-resistance efflux pumps, enriches PD-L1, and skews tumorassociated macrophages (TAMs) toward immunosuppressive M2 phenotypes. Therapeutic advances include porcupine (PORCN) inhibitors, β-catenin/TCF blockers, and Frizzled-directed antibodies now in phase I/II trials; however, their efficacy is limited by on-target toxicities and adaptive resistance. Integration of Wnt-centric gene signatures and machine-learning risk models now enables patient stratification and outcome prediction. Targeting context-dependent Wnt signaling, combined with rational combinatorial immunotherapy and TME reprogramming, offers a promising precisiononcology strategy to overcome therapeutic barriers in Wnt-driven malignancies.
Li et al. (Fri,) studied this question.