FIGURE 1.

Signaling pathways that regulate TAMs to promote tumor progression. Binding of canonical WNT ligands to the Frizzled family of membrane receptors results in activation of the canonical WNT pathway. β-Catenin then translocates to the nucleus, resulting in the release of β-catenin from the GSK3β complex (glycogen synthase kinase-3β)–AXIN complex (axis inhibition protein)–APC complex (adenomatous polyposis coli protein), where it is known to bind to the transcription factors Tcf (T cell factor) and Lef (lymphoid enhancer-binding factor) in order to activate genes that promote the growth of tumor progenitor cells. TGF-β proteins bind to the TGF-β family of receptors, leading to phosphorylation of the receptors and activation of SMAD complexes, which induce immune suppression. The TGF-β pathway is also known to collaborate with the PI3K–AKT pathway, which in turn triggers activation of the mTOR complex and the nuclear factor-κB signaling axis (NF-κB). TLR4 binds to its ligand and can phosphorylate the IkB protein via TRIF, dissociate NF-κB from the trimer, promotes its nuclear transfer, and then promotes the release of factors such as IL-1β, TNF-α, and IL-6, which are known to promote tumor growth and induce immune suppression. In addition, the binding of several cytokines such as IL-6 to their receptors triggers the phosphorylation and activation of Janus kinases (JAKs) as well as the signal transducer and activator of transcription proteins (STATs); STAT dimers promote the proliferation and survival of tumor cells and induce immune suppression.