Clinical development complexity of TGF-β inhibition: From fibrosis to cancer immunotherapy.

More than four decades have passed since the discovery of Transforming Growth Factor beta (TGF-β) in 1981, a pivotal cytokine with profound implications in cell biology and potential clinical interventions for physio-pathological processes including fibrosis, immune-related disorders, chronic infections, vascular alterations, and the progression of tumour growth through invasiveness and metastasis. However, the introduction of a specific inhibitor targeting this cytokine into the pharmaceutical market remains elusive. Various molecular entities and therapeutic strategies, including small molecules, peptides, recombinant proteins (such as specific antibodies), oligonucleotides, and cellular-based therapies have been devised and subjected to clinical trials. These target the specific TGF-β molecular pathway, either directly or indirectly. The combination of different drug types, routes of administration, and clinical indications has generated substantial data, emphasizing significant variability in patient outcomes. Efforts to enhance the effectiveness of cancer immunotherapy by combining TGF-β inhibitors with other drugs and modulating complementary molecular targets have been explored over the past few decades. This approach aims to translate the promising preclinical efficacy of TGF-β blockade into commercially available drugs that are suitable for a broad spectrum of clinical indications. However, a clear path to address the lack of discernible efficacy and overcome the associated marketing challenges has not yet emerged. This review provides a comprehensive overview of the clinical development and emerging trends in TGF-β inhibitors and modulatory strategies, offering novel perspectives for addressing this persistent challenge.