FIGURE 2.

The mechanism of canonical Wnt signaling and related pharmacological inhibitors. The binding of Wnt proteins to Frizzled (Fzd) family receptors can inhibit the phosphorylation of β‐catenin mediated by the destruction complex (mainly including glycogen synthase kinase 3β (GSK3β), Axin, and Dishevelled protein (DVL)) and thereby avoiding degradation. Stable β‐catenin will be translocated into the nucleus and trigger target gene transcription by interacting with TCF‐1 and other factors. Wnt target gene expression, such as MYCN, endows resistance to cancer drugs on tumor cells. However, GSK3β could be inhibited by forkhead box O3 (FOXO3), which is activated by tumor‐associated macrophage (TAM)‐secreted exosomal miR‐29a‐3p. Hypoxic conditions also enhance the proliferation and function of myeloid‐derived suppressor cells (MDSCs) and lead to an immunosuppressive environment. Agents targeting diverse proteins were validated to impede the activation of Wnt pathway, including anti‐Wnt mAbs and small molecular inhibitors of Wnt ligands, low‐density lipoprotein (LDL)‐related protein (LRP) inhibitors, small molecular inhibitors targeting β‐catenin, and tankyrase inhibitors that promote β‐catenin degradation.