The Transforming Growth Factor-β (TGF-β) signaling pathway plays a crucial role in regulating various essential biological processes, including embryonic development, tissue homeostasis, immune response modulation, and wound healing in multicellular organisms. TGF-β family ligands initiate signaling cascades by binding to specific cell surface receptors, regulating diverse cellular activities such as proliferation, phenotypic plasticity, migration, metabolism, and immune responses across various cell types. Upon ligand binding, TGF-β receptors undergo phosphorylation, activating intracellular SMAD proteins that translocate to the nucleus to influence gene expression. In addition to the canonical SMAD pathway, non-SMAD pathways are also activated, contributing to the wide range of cellular responses elicited by TGF-β signaling. This pathway’s versatility and extensive impact are evident across multiple physiological and pathological contexts. Dysregulation of the TGF-β signaling pathway is closely associated with the development and progression of numerous diseases. For instance, aberrant TGF-β signaling is a hallmark of fibrosis, characterized by excessive connective tissue deposition, leading to tissue scarring and impaired organ function. In cancer, TGF-β exhibits a dual role: it acts as a tumor suppressor in the early stages by inhibiting cell proliferation, but in advanced stages, it promotes tumor progression by facilitating epithelial-mesenchymal transition (EMT), invasion, and metastasis, as well as modulating the tumor microenvironment to evade immune surveillance. This review provides a comprehensive examination of the components and mechanisms underlying the TGF-β signaling pathway. It emphasizes the pathway’s critical role in embryonic development, including its involvement in germ layer formation, organogenesis, and body patterning. Additionally, the review highlights the significance of TGF-β signaling in stem cell biology, where it regulates stem cell maintenance, differentiation, and interactions within the stem cell niche. The review further delves into the implications of TGF-β signaling in various diseases, particularly its impact on immune regulation, fibrosis, and cancer progression. The ability of TGF-β to modulate immune responses is especially pertinent in chronic inflammatory conditions and cancer, where it can suppress anti-tumor immunity and foster an immunosuppressive environment conducive to tumor growth. Finally, the review explores emerging therapeutic strategies targeting the TGF-β signaling pathway for disease treatment. These strategies include the development of small molecule inhibitors, neutralizing antibodies, and receptor kinase inhibitors that aim to modulate the pathway’s activity. By targeting specific elements of the TGF-β signaling cascade, these therapeutic approaches hold significant promise for treating diseases associated with TGF-β dysregulation, offering potential for improved clinical outcomes. In sum, this review provides a comprehensive analysis of the TGF-β signaling pathway, elucidating its critical roles in both physiological and pathological contexts. It underscores the necessity for ongoing research to develop innovative therapeutic strategies, with the goal of leveraging the pathway’s potential for clinical applications. © 2024 Chinese Academy of Sciences. All rights reserved.
