Quantification of ferroptosis pattern in bladder carcinoma and its significance on immunotherapy

The role of ferroptosis in tumor development and therapy has been previously proved. Nonetheless, its potential role in tumor microenvironment (TME) and immunotherapy for bladder carcinoma remains unclear. Based on 38 ferroptosis-related genes, the characteristic of ferroptosis patterns and interactions with immune cell-infiltrating features in 2043 bladder cancer samples were systematically investigated. We further proposed the FerrScore to quantify the ferroptosis patterns for each patient. As results, three diverse ferroptosis patterns with distinct tumor-infiltrating immune cell features were established. By determination of ferroptosis patterns of each patient, we found that high FerrScore was related to lower proportion of luminal-papillary molecular subtype, more frequent TP53 mutations, activation of immunity and stroma, and lower 5-year survival. High FerrScore also seemed to be associated with decreased neoantigen load, tumor mutational burden and poorer response to anti-PD-L1/1 therapy. External verification in two immunotherapy cohorts showed FerrScore was an independent and effective prognostic factor for therapeutic effect and survival outcome. Overall, the present study indicated the ferroptosis strongly is closely correlated with TME diversity. Evaluation of the ferroptosis patterns may strengthen the cognition of TME immune cell infiltrations and guide more individualized immunotherapeutic strategies in bladder carcinoma.