Transforming Growth Factor‐β1 as a Biomarker of Malignant Behavior and <scp>PD</scp> ‐ <scp>L1</scp> Expression in Thymic Epithelial Tumors

The clinical significance and molecular mechanisms underlying tumor progression in thymic epithelial tumors (TETs) remain largely unclear. In this retrospective single-center study, we evaluated the prognostic value of transforming growth factor-beta 1 (TGF-β1) and its relationship with programmed death-ligand 1 (PD-L1) expression. A total of 92 patients with surgically resected TETs, including 79 thymomas and 13 thymic carcinomas, were included. Immunohistochemical analyses were performed to assess the expression of TGF-β1, PD-L1, phosphorylated Smad2 (pSmad2), and pSmad3. Associations between TGF-β1 expression and clinicopathological features were analyzed, and mechanistic interactions were investigated using two thymic carcinoma cell lines exposed to exogenous TGF-β1. High TGF-β1 expression was observed in 28% of patients and was significantly associated with advanced Masaoka stage (III/IV), shorter tumor doubling time (median 328 vs. 713 days, p = 0.042), and lower 5-year freedom from recurrence (FFR) rates (58.1% vs. 95.1%, p < 0.001, log-rank test). Coexpression of high TGF-β1 and PD-L1 was linked to the poorest prognosis (5-year FFR: 46.1%) and was identified as an independent predictor of recurrence (adjusted hazard ratio: 7.15; 95% confidence interval: 1.20-42.8). Immunohistochemically, TGF-β1 expression positively correlated with PD-L1 and pSmad2/3 expression. In vitro, TGF-β1 stimulation upregulated PD-L1 expression in a dose-dependent manner, accompanied by increased pSmad2/3 activation. These findings indicate that high TGF-β1 expression demarcates a biologically aggressive TET phenotype and, together with PD-L1, refines postoperative risk stratification, while its ability to drive PD-L1 via Smad signaling could support the blockade of these pathways as a potential therapeutic strategy.