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In conclusion, this study identified effective biomarkers for the prediction of immune checkpoint inhibitor treatment responsiveness in bladder cancer patients and provided new immunotherapeutic targets. In addition, we construct a risk prediction model which could stratify patients with bladder cancer and predict patient prognosis and ICB treatment responsiveness. We selected the important Hub genes as potential therapeutic targets, and validated the genes using genomic, transcriptomic, immunomic, and other multi-omics methods. Tumor immune dysfunction and exclusion (TIDE) scores were calculated using 2031 external bladder cancer samples for further validation. Transcriptome analysis confirmed that the high IMS score group had significant immune activation with better prognosis and higher immunotherapy responsiveness, which was a powerful biomarker for predicting the prognosis and responsiveness of ICB. The immune checkpoint inhibitor score (IMS) scoring system was constructed to predict the immunotherapy responsiveness. In this study, 348 pretreated metastatic urothelial cancer samples from the IMvigor210 cohort were used to identify important genes significantly associated with CD8+ T effector and immune checkpoint signatures. Immune-checkpoint blockade (ICB) has been routinely implemented to treat bladder cancer however, most patients have little or no clinical benefit.