Utilizing a novel mitochondrial-related gene signature for predicting the prognosis and immunological impact in bladder cancer

Mounting evidence highlights the critical role of mitochondrial dysfunction, driven by mitochondrial-related genes (MTRGs), in the development, progression, and therapeutic response of cancer. However, a comprehensive analysis linking specific Mitochondria-Related Gene Signature (MTRGS) to Bladder Cancer (BLCA) prognosis and immunotherapy efficacy remains largely unexplored. Therefore, this study aims to investigate the role of MTRGs in BLCA, construct and validate a novel MTRGs-based prognostic signature, and explore its potential for guiding personalized treatment strategies.

Leveraging transcriptomic and clinical data from The Cancer Genome Atlas (TCGA-BLCA) cohort, we constructed a mitochondrial-related risk score model using LASSO, univariate and multivariate Cox regression analyses. This model was subsequently validated in an independent Gene Expression Omnibus (GEO) dataset. We then employed integrated bioinformatics approaches (implemented in R with online databases) to characterize features of the tumor microenvironment (TME), immune cell infiltration, Gene Set Enrichment Analysis (GSEA), tumor mutational burden (TMB), and drug sensitivity across different risk groups. Additionally, using data from public databases, we further verified our findings through single-cell RNA sequencing (scRNA-seq) analyses.

Using 104 mitochondria-related differentially expressed genes (MTR-DEGs), unsupervised non-negative matrix factorization (NMF) clustering stratified BLCA patients into three molecular subtypes (Clusters 1-3). Survival analysis revealed that patients in Cluster 3 had significantly longer overall survival than those in Clusters 1 and 2. Our mitochondrial-related risk model incorporating six core genes (MAP1B, PYCR1, HSD3B1, KLK6, AKR1B15, and TAT) - exhibited robust prognostic capability (3-years AUC = 0.695 in TCGA-BLCA, 0.798 in GEO-GSE32894, 0.703 in GSE13507). The risk model revealed distinct immune infiltration patterns between high- and low-risk groups. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) and immunophenotype score (IPS) analyses demonstrated that integrating risk scores with stromal/immune signatures significantly enhanced immunotherapy benefit prediction across BLCA risk-subgroups. Crucially, the model demonstrated predictive power for therapy response: low-risk patients showed potential benefit from immune checkpoint inhibitors, while high-risk patients exhibited heightened sensitivity to specific chemotherapy agents or targeted therapies (e.g., Tozasertib, Gemcitabine) and may require intensified regimens.

This validated mitochondrial risk model delivers a clinically actionable biomarker for BLCA prognosis stratification and guides personalized therapeutic selection, enabling precision treatment intensification.