TGF-β in tumor development and progression: mechanisms and therapeutics

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine and participates in multiple cellular processes, such as cell development, proliferation, epithelial mesenchymal transition (EMT), and immune responses through SMAD-dependent or SMAD-independent signaling pathways. Notably, TGF-β signaling plays a dual role in tumors, acting as a potent tumor suppressor during early tumorigenesis by inducing apoptosis or cell-cycle arrest while promoting tumor transformation, progression and metastasis in advanced stage through multidimensional mechanisms. Moreover, it is abundant and functions as a master immune checkpoint in the tumor microenvironment (TME), fostering the development of numerous targeted therapies to rectify its aberrant activity in tumors in the past decades. Thus, a comprehensive overview of the pathologic roles, molecular mechanisms and therapeutic potentials of TGF-β signaling in tumors will benefit both the basic and clinical cancer research. Here, we review the complex biology and context-dependent functions of the TGF-β superfamily in regard to tumor, highlighting how it regulates the latter's development, growth, and dissemination by mainly targeting tumor cells, tumor-associated fibroblasts and various immune cells. We also summarize recent advances in the preclinical and clinical development of different types of TGF‑β‑targeting agents, and discuss their therapeutic potentials and challenges as well as approaches to improve the safety and efficacy of TGF-β pathway-targeted therapy in cancers. Through the summary of known knowledge and the latest updates, this review may provide a general picture on the biological functions of TGF-β in tumors, and facilitate the clinical implications of TGF-β-targeted therapy in tumor patients.