肿瘤细胞治疗研究
英文原题：Downregulation of THRB drives immune microenvironment suppression and poor outcomes, acting as a dual biomarker for clear cell renal cell carcinoma.
THRB下调与ccRCC的不良预后、免疫抑制微环境及靶向治疗耐药相关。这些发现提示其作为双重生物标志物的潜力，意味着THRB缺失可能促进免疫失调和治疗耐药。恢复THRB介导的通路可能提供新的治疗策略，但其对免疫治疗的预测价值尚需未来临床验证。
透明细胞肾细胞癌（ccRCC）常对靶向治疗和免疫治疗产生耐药，因此亟需预测性生物标志物。甲状腺激素受体β（THRB）是位于3p21-25的核转录因子，在其他癌症中显示出抑癌作用，但其在ccRCC中的免疫调节功能尚不清楚。
利用TCGA-KIRC数据（535例肿瘤，72例正常组织）及验证队列（GSE46699/53757），我们通过差异表达分析（limma）、生存分析（Kaplan-Meier/Cox回归）、免疫浸润分析（CIBERSORT/ESTIMATE）、功能富集分析（GO/KEGG/GSEA）及药物敏感性分析（pRRophetic），分析了THRB的表达、临床相关性及免疫关联。
THRB在ccRCC及其他11种癌症中显著下调（P < 0.05），与晚期分期/分级（P < 0.001）及较差的生存期（OS HR = 2.33，DSS HR = 3.43；P < 0.001）相关。多因素分析证实其独立预后价值（HR = 0.69，P = 0.007）。在功能上，THRB与免疫调节（T细胞活化、PD-1/PD-L1通路）及不同的免疫浸润模式相关。高THRB肿瘤富集静息免疫细胞和M2巨噬细胞，而低THRB肿瘤显示较高比例的CD8⁺ T细胞和调节性T细胞（Tregs），并伴有T细胞耗竭标志物表达升高（均P < 0.01）。这提示THRB在塑造免疫景观中具有复杂作用。THRB与TMB（r=-0.26，P < 0.001）及抑制性检查点（LGALS9、CD70）呈负相关，但与VTCN1呈正相关。计算机分析预测，低THRB患者可能对舒尼替尼/帕唑帕尼表现出降低的敏感性（较高的IC50，P < 0.001）。
BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
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