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. 2019 Nov 11;12:9527–9538. doi: 10.2147/OTT.S224013

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© 2019 Bai et al.

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TGF-β signaling pathway and its role in tumor immune microenvironment. TGF-β signal is transduced by TGF-β receptor complex which consists of TGF-βI receptors and TGF-βII receptors (TGF-βRI and TGF-βRII). Firstly, extracellular TGF-β binds to TGF-βRII homodimer which further complex with TGF-βRI homodimer. Following TGF-β engagement, TGF-βRII homodimer phosphorylates the intracellular domain of TGF-βRI. The engagement of TGF-β receptor complex recruits receptor Smad (R-Smad) molecules Smad2 and 3 to the intracellular domain of TGF-βRI. Subsequently, Smad2 and 3 are phosphorylated which then form a trimeric complex with Smad4. The trimeric Smad complex could translocate to nuclear and regulate gene expression. Besides, phosphorylated Smad2 and 3 could also form a trimeric complex with TIF1γ to regulate the expression of targeting genes. Apart from classic Smad pathway, TGF-β signal could also be transduced by some Smad-independent pathways such as PI3K, MAPK, and Rho GTPase pathways. TGF-β signaling pathway has a substantial influence on various immune cells including downregulating the cytotoxicity of effector T cells and NKs, promoting the apoptosis of effector T cells, inducing the differentiation towards Tregs, hampering the antigens presentation of DCs.

Abbreviations: NK, natural killer cell; CAF, cancer-associated fibroblast; MHC, major histocompatibility complex; IDO, indoleamine-2, 3-dioxygenase; Id1, inhibitor of differentiation 1; Treg, regulatory T cell.