Turning TGF-β Signaling Against Prostate Cancer: Biomarker Potential, Therapeutic Opportunities and Translational Barriers

Transforming growth factor-β (TGF-β) signaling plays a complex and context-dependent role in prostate cancer, functioning as a tumor suppressor in early disease while promoting epithelial plasticity, immune evasion, metastatic progression, and treatment resistance in advanced tumors. Using a systematic review of the literature, we examined the biological, clinical, and translational significance of TGF-β pathway dysregulation in prostate cancer, with a particular focus on biomarker development, therapeutic opportunities, and barriers to clinical implementation. Evidence from human studies suggests that altered TGF-β expression, circulating biomarkers, and pathway-associated genetic variation are associated with aggressive disease features, biochemical recurrence, metastasis, and adverse clinical outcomes. However, translation into clinically useful biomarkers has been hindered by substantial heterogeneity in analytes, assay methodologies, patient populations, and outcome measures. Mechanistic and preclinical studies further demonstrate that TGF-β signaling contributes to epithelial-mesenchymal transition, tumor microenvironment remodeling, immune suppression, and resistance to androgen receptor-directed therapies, chemotherapy, and radiotherapy. These findings have stimulated the development of TGF-β-targeted therapeutic strategies, particularly in combination with immunotherapies, DNA damage response-targeted agents, and established systemic treatments. Nevertheless, the pleiotropic and stage-specific functions of TGF-β, together with concerns regarding toxicity and patient selection, present significant challenges to therapeutic intervention. Future progress will depend on the development of robust and standardized biomarkers, prospective validation in clinically relevant cohorts, and trial designs that incorporate pathway activity, tumor microenvironmental context, and disease stage into treatment selection. Collectively, current evidence positions TGF-β signaling as a promising but biologically complex target for advancing precision medicine in prostate cancer.