mTORC-Driven Immunogenomic Reprogramming Shapes Prognosis and Therapeutic Vulnerabilities in Unfavorable Histology Wilms Tumor

Unfavorable Histology Wilms Tumor (UFH-WT) is a high-risk pediatric renal malignancy with poor prognosis, and the mTORC pathway's role in its heterogeneity, immune remodeling, and therapeutic vulnerability remains unclear, restricting its clinical application as a prognostic biomarker and therapeutic target. Integrative multiomics analysis of transcriptomic, genomic, and clinical data was performed on three UFH-WT cohorts (TARGET-WT, GSE4530, GSE66405). Unsupervised clustering was used to identify mTORC-related subtypes; machine learning was applied to construct an mTORC-driven gene signature. The associations between mTORC activity and immune infiltration, genomic instability were analyzed, and drug sensitivity was predicted. Subtypes and prognosis: Two mTORC subtypes were identified. The mTORC-high subtype had inferior 5-year overall survival (OS) (42.3% vs. 68.7%, P = 0.044) and more prominent adverse genetic features (TP53 mutation: 38.7% vs. 19.4%; 1q gain: 45.2% vs. 25.8%, P < 0.05). Gene signature and prognostic model: A 4-gene signature (BTG2, LHX1, PKIA, RGS7) was constructed, which effectively stratified patients (5-year OS AUC: 0.632 [TARGET-WT], 0.589 [GSE4530], 0.618 [GSE66405]) and outperformed clinical variables. A nomogram integrating this signature and clinical parameters improved prognostic evaluation (2-year AUC = 0.705). Mechanistic associations: mTORC hyperactivation upregulated oncogenic pathways (nucleocytoplasmic transport, chromatin remodeling), suppressed proinflammatory signaling (TNF, NF-κB), reshaped the immunosuppressive tumor microenvironment (increased monocyte infiltration, decreased dendritic cells, upregulated PD-L1/CTLA-4), and increased tumor mutation burden (TMB: 3.2 vs. 1.8 mut/Mb, P = 0.003). Drug sensitivity: High-risk tumors were more sensitive to mTOR inhibitors (e.g., AZD8055, IC ₅₀  = 0.42 µM vs. 0.71 µM), DNA damage modulators, and microtubule agents. mTORC signaling drives UFH-WT aggressiveness through immune evasion and genomic instability. The 4-gene signature and integrated nomogram enable risk stratification of UFH-WT, and the identified therapeutic vulnerabilities provide guidance for precision therapy.