TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity

Transforming growth factor-β (TGFβ) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and non-SMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In non-cancer and early-stage cancer cells, TGFβ signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFβ may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFβ expression leads to the instigation and development of cancer. Therefore, suppressing TGFβ signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFβ signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFβ. Nonetheless, targeting the activation of TGFβ signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFβ are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFβ signaling in stromal and cancer cells. Here, we discussed the critical role of TGFβ in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFβ inhibitory molecules in the treatment of cancer.