The tumor-microenvironment-associated prognostic gene TIGIT promotes malignant phenotypes in esophageal carcinoma

BACKGROUND: Previous studies have shown that tumor immune microenvironment related markers are associated with tumor prognosis. However, few studies have explored the prognostic value of tumor cell surface biomarkers (e.g., CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT) in resectable ESCC. METHODS: We retrospectively analyzed 69 ESCC patients who underwent complete resection at Zhejiang Cancer Hospital. Using multiplex immunofluorescence histochemistry, we evaluated the expression of CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT in tumor and immune microenvironments and their associations with clinical outcomes. Triple-color immunofluorescence confirmed TIGIT expression in ESCC tissues. Functional roles of TIGIT were further investigated via RNA-seq, real-time PCR, WB, CCK-8 assays, transwell assays, and flow cytometry. RESULTS: The median follow-up was 47.7 months. High expression was most frequent for CD8 (52.2%), followed by TIM3 (29.0%), PD-L1 (17.4%), LAG3 (24.6%), TIGIT (20.3%), and CD163 (14.5%). Median DFS was 17.4 months and OS was 26.8 months. Higher TIGIT expression correlated with shorter DFS and OS. Stratification by TIGIT-to-PAN-CK ratio confirmed that higher tumor-cell TIGIT was an unfavorable prognostic indicator. Functional analyses showed that TIGIT knockdown reduced ESCC cell migration, invasion, and proliferation, and altered cell cycle distribution with S-phase accumulation. RNA-sequencing implicated cytokine-receptor interactions and the JAK-STAT signaling axis in TIGIT-mediated functions. CONCLUSIONS: TIGIT, along with PD-L1 and CD163, is a potential prognostic marker for resectable ESCC. TIGIT is not only expressed in immune cells but also in ESCC tumor cells, suggesting its potential as a biomarker and therapeutic target. Further mechanistic studies are warranted to elucidate the downstream signaling pathways and validate the mechanisms of TIGIT in ESCC.