Transforming Growth Factor-Beta Signaling in Cancer: Therapeutic Implications, Challenges, and Pathways to Progress

The transforming growth factor-β (TGF-β) family consists of evolutionarily conserved cytokines that regulate various physiological processes across nearly all tissue and cell types. While TGF-β signaling plays a critical role in immune homeostasis and tissue repair, its dysregulation is implicated in multiple diseases, particularly cancer. Given its dual role in tumor suppression and promotion, TGF-β has emerged as a promising yet challenging therapeutic target. Preclinical studies have demonstrated significant tumor inhibition through TGF-β signaling blockade using diverse classes of inhibitors. However, despite extensive research and clinical trials spanning over two decades, no TGF-β inhibitors have been approved for cancer therapy, underscoring a significant disconnect between preclinical promise and clinical efficacy. This review systematically examines the tumorigenic mechanisms driven by TGF-β and evaluates the therapeutic landscape of anti-TGF-β inhibitors, including receptor kinase inhibitors, neutralizing antibodies, bifunctional ligand traps, integrin-mediated TGF-β therapy, antisense oligonucleotides, TGF-β-targeted vaccines, and various combination strategies. By comparing preclinical and clinical findings, we highlight key challenges and propose novel approaches to improve the translational success of TGF-β-targeted therapies. These insights provide a foundation for optimizing future research and advancing the clinical application of TGF-β inhibitors in oncology.