Exploring the potential of TGFβ as a diagnostic marker and therapeutic target against cancer

Transforming Growth Factor-beta (TGF-β) is a multifunctional cytokine that exerts its biological effects through a complex process of activation and signaling. Initially synthesized in an inactive form bound to latency-associated peptide (LAP), TGF-β requires release from the extracellular matrix via proteolytic cleavage or integrin-mediated activation to engage with its receptors. Once active, TGF-β binds to type II receptor (TβRII), which then phosphorylates and activates type I receptor (TβRI), triggering downstream signaling cascades, including both Smad-dependent and non-Smad pathways. These signaling cascades regulate key processes like cell growth, differentiation, migration, and immune response modulation, thereby influencing tumor development, progression, and treatment outcomes. This review discusses the complex signaling pathways of TGF-β in cancer, including its interactions with other signaling molecules and its involvement in epithelial-mesenchymal transition (EMT) and in evading immune surveillance. Moreover, dysregulated TGF-β signaling due to alterations in receptor expression, mutations in key signaling proteins such as TβRII and Smads, and aberrant activation of non-canonical pathways, contributes significantly to tumor aggressiveness, metastasis, and therapy resistance. The article emphasizes the potential of TGF-β as a diagnostic biomarker for cancer, highlighting its use in early detection, prognosis assessment, and monitoring treatment response. Additionally, it underscores various therapeutic strategies targeting TGF-β, such as small molecule inhibitors, monoclonal antibodies, immunotherapies, and evaluates their efficacy and limitations in preclinical and clinical settings. Finally, the review provides a comprehensive analysis of TGF-β’s role as both a diagnostic tool and a therapeutic target, while also discussing the challenges and opportunities in targeting TGF-β signaling for improving cancer treatment outcomes.