Integrated Ferroptosis and Immune Features Are Associated With Overall Survival in Bladder Urothelial Carcinoma: A TCGA-Based Analysis.

OBJECTIVES

To investigate the prognostic value of ferroptosis-related and immune-related transcriptional features in bladder urothelial carcinoma (BUC) and to evaluate whether their integration provides incremental prognostic information beyond conventional clinical factors.

METHODS

Transcriptomic and clinical data of patients with BUC were obtained from The Cancer Genome Atlas (TCGA) as the training cohort. Ferroptosis and immune scores were constructed based on predefined gene sets using a z-score-based averaging method. Associations with overall survival were evaluated using Kaplan-Meier analysis and multivariable Cox regression with adjustment for age and pathological stage. Model performance was assessed using concordance index (C-index), likelihood ratio testing, and bootstrap internal validation. External validation was performed in independent cohorts (GSE13507 and GSE32894). Nonlinear relationships were examined using restricted cubic spline analysis, and sensitivity analyses were conducted by incorporating additional clinicopathologic variables.

RESULTS

Neither ferroptosis nor immune scores alone were significantly associated with overall survival in Kaplan-Meier analyses. Multivariable Cox regression showed a directionally protective effect of immune score and a non-significant risk trend for ferroptosis score. Integration of ferroptosis and immune features resulted in modest improvement in prognostic performance compared with clinical models alone. These findings were consistent across external validation cohorts. Restricted cubic spline analysis revealed a nonlinear association for immune score but not for ferroptosis score. Sensitivity analyses incorporating tumor grade yielded similar results, supporting robustness of the findings.

CONCLUSION

Ferroptosis and immune transcriptional features provide limited but consistent incremental prognostic information in bladder urothelial carcinoma. These findings are exploratory and hypothesis-generating, suggesting that integration of ferroptosis and immune biology may offer complementary insights but is not yet sufficient for clinical application.