TGF-beta inhibitors in cancer therapy: a review of the TGF-beta signal transduction pathway and current developments

Authors

  • Shun-Ban Tai Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Armed Forces General Hospital, Kaohsiung 81342, Taiwan ROC https://orcid.org/0009-0007-5184-1917
  • Jenq-Lin Yang Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ROC https://orcid.org/0000-0002-9897-8087
  • Pei-Feng Liu Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80756, Taiwan ROC https://orcid.org/0000-0002-7849-8940
  • Chun-Lin Chen Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC. Tel: +886-7-5252000 ext 3629. Fax: +886-7-5253609. E-mail: chunlinchen@mail.nsysu.edu.tw https://orcid.org/0000-0003-1519-2642

DOI:

https://doi.org/10.17179/excli2026-9381

Keywords:

TGF-β signaling, cancer therapy, TGF-β inhibitors, tumor microenvironment, drug repurposing, combination therapy

Abstract

Transforming growth factor-β (TGF-β) belongs to a family of structurally and functionally related cytokines that play essential roles in embryonic development, tissue homeostasis, and cell fate regulation. Dysregulation of TGF-β signaling contributes to a broad spectrum of diseases, including cancer, fibrosis, and immune disorders. In cancer, TGF-β exhibits a context-dependent dual role, functioning as a tumor suppressor during early stages while promoting invasion, metastasis, escape from immune surveillance, and tumor microenvironment remodeling in advanced-stage cancer through effects on stromal cells, extracellular matrix deposition, and angiogenesis. This functional duality makes therapeutic targeting both attractive and challenging. Although current strategies mainly focus on ligand neutralization or receptor kinase inhibition, accumulating evidence indicates that TGF-β activity is also regulated beyond the receptor level, including receptor trafficking, co-receptor function, nucleocytoplasmic shuttling, indirect pathway modulation, and epigenetic regulation. In this review, we emphasize regulatory mechanisms that can be modulated by existing drugs, clinical candidates, or experimentally tractable compounds, rather than providing an exhaustive overview of the broader regulatory landscape of TGF-β signaling. We further highlight opportunities for drug repurposing and discuss how synergistic combination strategies may improve therapeutic efficacy and overcome resistance in TGF-β–driven cancers, supporting a broader therapeutic framework beyond canonical receptor inhibition.

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Published

2026-04-28

How to Cite

Tai, S.-B., Yang, J.-L., Liu, P.-F., & Chen, C.-L. (2026). TGF-beta inhibitors in cancer therapy: a review of the TGF-beta signal transduction pathway and current developments. EXCLI Journal, 25, 550–586. https://doi.org/10.17179/excli2026-9381

Issue

Vol. 25 (2026)

Section

Review articles

Categories

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Copyright (c) 2026 Shun-Ban Tai, Jenq-Lin Yang, Pei-Feng Liu, Chun-Lin Chen

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