Transforming Growth Factor beta (TGF-β) is a cytokine belonging to the growth factors superfamily, that presents three different isoforms in mammals. Structurally, TGF-β exists as a homodimer and exerts autocrine, paracrine, and endocrine activities crucial from embryogenesis to adult homeostasis (Massagué & Sheppard, 2023). Among its isoforms, TGF-β1 holds significant biological activity, typically secreted within inactive protein complexes that undergo controlled activation in the extracellular matrix and cell membrane multiprotein complexes (Massagué and Sheppard, 2023, Roberts et al., 1991).

TGF-β serves as a multifunctional cytokine, pivotal in various cellular processes including proliferation, migration, differentiation, apoptosis, and regulatory activities such as profibrotic, proangiogenic, and immunomodulatory functions. Its involvement in tumour development and metastasis underscores its pleiotropic nature, exhibiting context-dependent properties, and occupying a high position in the cytokine regulatory hierarchy (Massagué and Sheppard, 2023, Deng et al., 2024). Dysregulation of TGF-β signalling contributes to diseases such as cancer, fibrosis, and autoimmune disorders, leading to its exploration in clinical trials as a potential therapeutic intervention and biomarker (David and Massagué, 2018, Liu et al., 2021).

Clinical trials have investigated TGF-β inhibitors for their potential anti-fibrogenic, anti-tumour, and immunomodulatory effects, particularly in blocking pathways that promote tumour growth and immune evasion. Combination therapies involving TGF-β inhibitors along with chemotherapy or immunotherapy aim to enhance treatment effectiveness (Colak & Ten Dijke, 2017). Additionally, the role of TGF-β in fibrosis underscores its significance in treating fibrotic diseases of various organs, while its involvement in immune system regulation positions it as a target for autoimmune disease modulation and as a reference factor for disease evolution (De Gramont et al., 2017, Meng et al., 2016, Hawinkels and Ten Dijke, 2011, Yingling et al., 2004). TGF-β levels and activity may also serve as biomarkers in certain diseases, with ongoing trials exploring their utility in patient stratification, treatment monitoring, and outcome prediction (Sun et al., 2016, Fernandez and Eickelberg, 2012).

However, the clinical development environment for TGF-β modulation presents challenges, given its dual role as both a tumour suppressor and promoter of tumour progression in cancer and anti- and pro-inflammatory activities in immunity and autoimmunity (Massagué and Sheppard, 2023, Massague, 2008, De Streel and Lucas, 2021a). Achieving therapeutic balance without adverse effects is complex. Furthermore, the intricate activation processes of TGF-β from latent protein complexes, coupled with its short half-life in the free form (2–3 min compared to 90 min of the latent form), pose challenges for inhibition and detection (Shi et al., 2011, Roberts, 1998).

The evolving field of TGF-β-targeted therapies highlights the relevance of considering the disease context, patient context and subpopulations, dosage timing, and disease stage for successful outcomes. Ongoing and upcoming clinical trials continue to shed light on the role of TGF-β in various diseases, thereby contributing to our understanding of its therapeutic potential.