Integrative Analysis of TNFRSF18 in Immunogenomics: Implications as a Predictive Biomarker and Therapeutic Target in Precision Immunotherapy

Tumor Necrosis Factor Receptor Superfamily Member 18 (TNFRSF18/GITR) plays a crucial role in tumor immunity and inflammatory pathways. However, its comprehensive role in pan-cancer contexts has not been fully elucidated. Through integrated analyses of multiple databases were conducted. Analyses covered TNFRSF18 expression, prognostic associations, pathway enrichment, and immunomodulatory functions, with clinical validation via immunohistochemistry on human-derived specimens. Pan-cancer profiling showed elevated TNFRSF18 expression in tumor-infiltrating immune cells, but varied survival associations across cancer types. Functional analyses associated TNFRSF18 with immune-regulatory pathways. Its expression was strongly correlated with regulatory T cell infiltration and immunomodulator levels. Single-cell RNA sequencing confirmed selective overexpression of TNFRSF18 in Tregs from renal (KIRC), esophageal (ESCA), and endometrial (UCEC) cancers. Immunogenomic analyses indicated that TNFRSF18 predicts response to immune checkpoint inhibitors, with accuracy comparable to that of PD-L1. In the KIRC cohort, TNFRSF18 exhibited superior predictive performance for prognosis compared to conventional clinical biomarkers. Spatial mapping revealed that TNFRSF18 co-localizes with PD-1 and CTLA-4 on activated T regulatory cells. These findings support its role in establishing an immune-inhibitory microenvironment, establishing TNFRSF18 as a cancer-type-specific biomarker for predicting therapeutic response and guiding precision immunotherapy.