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

ABSTRACT 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.