Comprehensive analysis of the TGF-β signaling pathway: molecular mechanisms, disease drivers, and frontiers in clinical translation

Transforming growth factor-β (TGF-β) is one of the most complex and context-dependent cytokines in the immune system. Its signaling pathway regulates differentiation, functions, and microenvironment-specific adaptations of immune cells through Smad-dependent and Smad-independent pathways. In normal physiological conditions, TGF-β maintains immune tolerance, regulates T-cell fate determination, and participates in tissue repair. In pathological conditions, aberrant TGF-β signaling drives fibrosis, tumor immune evasion, and chronic inflammatory responses. In recent years, innovative technologies such as single-cell omics and spatial transcriptomics have revealed the dynamic characteristics of TGF-β signaling in different cell lineages and microenvironments. These techniques have deepened the understanding of its molecular circuits and immune regulatory networks. Therapeutic strategies targeting TGF-β, including receptor kinase inhibitors, bispecific antibodies, and nanotechnology-based delivery systems, have shown potential in disease models such as fibrosis and tumors, but still face challenges such as toxicity, side effects, and disease stage dependence. This article reviews the multidimensional mechanism of TGF-β signaling in immune homeostasis, fibrosis, and tumor progression; assesses its prospects and limitations as a therapeutic target; and proposes future directions for clinical translation through patient stratification and disease staging, precise nanodelivery, and combination therapy, providing a theoretical basis for precise intervention in immune-related diseases.