CLTC expression in oral squamous cell carcinoma: insights into prognostic value and immune microenvironment modulation

BACKGROUND: Oral squamous cell carcinoma (OSCC) has a poor prognosis because of its high metastatic potential and frequent chemoresistance. Although CLTC is aberrantly expressed and involved in fusion events in several tumors, its role in OSCC remains poorly defined. METHODS: We integrated transcriptomic and clinical data from TCGA and GEO, scRNA-seq data, immune infiltration analysis, ligand-receptor based cell-cell communication analysis, drug sensitivity prediction, molecular docking, and in vitro functional validation to evaluate CLTC expression, prognostic value, and its association with the OSCC immune microenvironment. RESULTS: CLTC was significantly overexpressed in OSCC and several other cancers. High CLTC expression was associated with poorer survival and improved prognostic stratification when combined with tumor mutation burden (TMB). Immune analyses showed that high CLTC expression was associated with reduced CD8 + T-cell infiltration, decreased cytotoxic activity, and increased immune exclusion- and suppression-related signatures. Single-cell analysis showed that CLTC was broadly expressed across OSCC cell populations, with relatively high expression in epithelial, inflammatory epithelial, macrophage, inflammatory macrophage, and endothelial cells. Macrophage-centered communication analysis further revealed prominent MIF-, CXCL-, and SPP1-related signaling interactions between macrophages and tumor, stromal, and immune cell populations. Drug sensitivity prediction and molecular docking suggested potential associations between CLTC expression and responses to several chemotherapeutic agents, although these computational results indicate possible physical interactions rather than confirmed functional drug effects. In vitro experiments confirmed that CLTC was upregulated in OSCC tissues and that CLTC knockdown suppressed SCC25 cell proliferation, migration, and invasion. CONCLUSION: CLTC may serve as a prognostic biomarker in OSCC and may contribute to tumor progression by promoting malignant cellular phenotypes and immunosuppressive remodeling of the tumor microenvironment. Future mechanistic studies are required to determine whether CLTC directly regulates chemotherapy response through clathrin-mediated trafficking, receptor recycling, adhesion signaling, or tumor-immune interactions.