Downregulation of THRB drives immune microenvironment suppression and poor outcomes, acting as a dual biomarker for clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) frequently resists targeted and immune therapies, necessitating predictive biomarkers. Thyroid hormone receptor beta (THRB), a nuclear transcription factor at 3p21-25, shows tumor-suppressive roles in other cancers but its immunomodulatory function in ccRCC remains unclear. Using TCGA-KIRC data (535 tumors, 72 normals) and validation cohorts (GSE46699/53757), we analyzed THRB expression, clinical correlations, and immune associations via differential expression (limma), survival analysis (Kaplan-Meier/Cox regression), immune infiltration (CIBERSORT/ESTIMATE), functional enrichment (GO/KEGG/GSEA), and drug sensitivity (pRRophetic). THRB was significantly downregulated in ccRCCand 11 other cancers (P < 0.05), correlating with advanced stage/grade (P < 0.001) and poorer survival (OS HR = 2.33, DSS HR = 3.43; P < 0.001). Multivariate analysis confirmed its independent prognostic value (HR = 0.69, P = 0.007). Functionally, THRB associated with immune regulation (T-cell activation, PD-1/PD-L1 pathways) and distinct immune infiltration patterns. High-THRB tumors were enriched for resting immune cells and M2 macrophages, while low-THRB tumors showed higher fractions of CD8⁺ T cells and regulatory T cells (Tregs), along with elevated expression of T-cell exhaustion markers (all P < 0.01). This suggests a complex role for THRB in shaping the immune landscape. THRB negatively correlated with TMB (r=-0.26, P < 0.001) and inhibitory checkpoints (LGALS9, CD70), but positively with VTCN1. In silico analysis predicted that low-THRB patients might exhibit reduced sensitivity to sunitinib/pazopanib (higher IC50, P < 0.001). THRB downregulation is associated with poor prognosis, an immunosuppressive microenvironment, and resistance to targeted therapies in ccRCC. These findings suggest its potential as a dual biomarker, implying that THRB loss may contribute to immune dysregulation and therapy resistance. Restoring THRB-mediated pathways may offer novel therapeutic strategies, though its predictive value for immunotherapy requires future clinic validation.