The role of WNT signaling in papillary thyroid cancer: Mechanisms, epigenetic regulation, therapeutic resistance, and emerging clinical strategies.

WNT signaling is a key pathway that regulates cell growth, differentiation, and tissue balance. In papillary thyroid cancer (PTC), abnormal activation of both canonical (β-catenin-dependent) and non-canonical pathways contributes to tumor progression and therapy resistance. These mechanisms include reduced response to radioactive iodine (RAI), kinase inhibitors, and immunotherapies. This review outlines how WNT dysregulation drives processes such as epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) plasticity, and crosstalk with major oncogenic pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and transforming growth factor-β (TGF-β). We also examine the role of the tumor microenvironment (TME), where factors like fibroblast-derived cytokines and hypoxia reinforce WNT-driven resistance. Epigenetic modifiers, exosomal WNT ligands, and noncoding RNAs emerge as additional regulators. Finally, we discuss clinical implications, highlighting the value of WNT biomarkers in trials and the potential of combining WNT inhibition with RAI sensitization, MAPK blockade, or immune checkpoint therapy.