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Wnt Signaling in Tumorigenesis: From Molecular Mechanisms to Precision Therapeutic Targets

Guizhen Lyu1, Yuxin Zhang2, Dongbing Li3

  • 1Dongguan Key Laboratory of Clinical Medical Test Diagnostic Technology for Oncology, Dongguan Labway Clinical Laboratory Co., Ltd., Dongguan 523429, Guangdong, China.

Current Topics in Medicinal Chemistry
|February 26, 2026
PubMed

Insights

The Wingless (Wnt) signaling pathway drives cancer by promoting tumor growth and spread. Targeting Wnt signaling, combined with immunotherapy, offers a new precision oncology strategy for difficult-to-treat cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • The Wingless/Integrated (Wnt) signaling pathway is crucial for development and tissue homeostasis.
  • Dysregulation of Wnt signaling is a key driver in various cancers, impacting embryogenesis, stem-cell renewal, and tissue repair.
  • Recent multi-omic and translational studies highlight Wnt pathway's role in tumor initiation, maintenance, and dissemination.

Purpose of the Study:

  • To review how canonical and non-canonical Wnt signaling cascades initiate, maintain, and spread tumors across diverse organs.
  • To summarize Wnt pathway's role in cancer stem-cell traits, metastasis, and therapeutic resistance.
  • To explore emerging therapeutic strategies targeting Wnt signaling in malignancies.

Main Methods:

  • Integration of recent multi-omic and translational studies.
  • Analysis of mutational hotspots (e.g., APC, CTNNB1, RNF43, ZNRF3) and ligand-driven circuits.
  • Examination of tumor-specific expression profiles and pathway crosstalk (e.g., TGF-β, Notch, EMT).

Main Results:

  • Wnt signaling dysregulation, through mutations or tumor microenvironment interactions, drives tumor progression and heterogeneity.
  • Wnt pathway crosstalk with TGF-β, Notch, and EMT sustains cancer stem cells, metastasis, and resistance to therapies.
  • Wnt signaling mechanistically promotes multidrug resistance, PD-L1 enrichment, and immunosuppressive tumor microenvironments.
  • Emerging therapies targeting Wnt signaling show promise but face challenges with toxicity and resistance.

Conclusions:

  • Targeting context-dependent Wnt signaling, alongside immunotherapy and TME reprogramming, is a promising precision oncology strategy.
  • Wnt-centric gene signatures and machine learning enable patient stratification and outcome prediction for Wnt-driven cancers.
  • Overcoming therapeutic barriers in Wnt-driven malignancies requires integrated approaches targeting Wnt signaling and its associated pathways.
Keywords:
Cancer stem cellsTargeted therapy.Treatment resistanceTumor microenvironmentTumorsWnt signaling pathway

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