Dynamics of transforming growth factor β signaling and therapeutic efficacy

Transforming growth factor β (TGFβ) is a multifunctional cytokine, and its signalling responses are exerted via integrated intracellular pathways and complex regulatory mechanisms. Due to its high potency, TGFβ signalling is tightly controlled under normal circumstances, while its dysregulation in cancer favours metastasis. The recognised potential of TGFβ as a therapeutic target led to emerging development of anti-TGFβ reagents with preclinical success, yet these therapeutics failed to recapitulate their efficacy in experimental settings. In this review, possible reasons for this inconsistency are discussed, addressing the knowledge gap between theoretical and actual behaviours of TGFβ signalling. Previous studies on oncogenic cells have demonstrated the spatiotemporal heterogeneity of TGFβ signalling intensity. Under feedback mechanisms and exosomal ligand recycling, cancer cells may achieve cyclic TGFβ signalling to facilitate dissemination and colonisation. This challenges the current presumption of persistently high TGFβ signalling in cancer, pointing to a new direction of research on TGFβ-targeted therapeutics.