Authors
Shun-Ban Tai, Jenq-Lin Yang, Pei-Feng Liu, Chun-Lin Chen
Published in
EXCLI journal. Volume 25. Pages 550-586. Epub Apr 28, 2026.
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. See also the graphical abstract(Fig. 1).
PMID:
42318498
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.
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