Disulfidptosis characterizes the tumor microenvironment and predicts immunotherapy sensitivity and prognosis in bladder cancer

Background: Bladder cancer (BLCA) is prone to metastasis and has poor prognosis with unsatisfactory treatment responsiveness. Disulfidptosis is a recently discovered, novel mode of cell death that is closely associated with human cancers. However, a comprehensive analysis of the relationship between disulfidptosis and BLCA is lacking. Therefore, this study aimed to explore the potential effect of disulfidptosis on BLCA and identify a biomarker for evaluating the prognosis and immunotherapy of patients with BLCA. Material and methods: We acquired BLCA RNA sequencing data from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) cohort (containing 19 normal samples and 409 tumor samples) and the GES39281 cohort (containing 94 tumor samples) which were used for external validation of the signature. Initially, we performed unsupervised consensus clustering to explore disulfidptosis-related subgroups. We then conducted functional enrichment analysis on these subgroups to gain insights into their biological significance and evaluate their immunotherapy response and chemotherapy sensitivity. Next, we conducted Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression to construct a prognostic signature in the TCGA training set for prognosis-related differentially expressed genes (DEGs) in the disulfidptosis-related subgroups. Subsequently, we used a receiver operating characteristic (ROC) curve and independent prognostic analysis to validate the predictive performance of the signature in the TCGA testing and the GES39281 cohorts. Finally, we explored the therapeutic value of this signature in patients with BLCA, in terms of immunotherapy and chemotherapy. Result: In this study, we obtained two subgroups: DRG-high (238 samples) and DRG-low (160 samples). The DRG-high group exhibited a poor survival rate compared to the DRG-low group and had a significant association with tumor grade, stage, and metastasis. Additionally, several pathways related to cancer and the immune system were enriched in the high-DRG group. Moreover, the DRG-high group exhibited higher expression of PD1 and CTLA4 and had a better response to immunotherapy in patients with both PD1 and CTLA4 positivity. Conversely, the DRG-high group was more sensitive to common chemotherapeutic agents. A prognostic signature was created, consisting of COL5A1, DIRAS3, NKG7, and POLR3G and validated as having a robust predictive capability. Patients in the low -risk -score group had more immune cells associated with tumor suppression and better immunotherapy outcomes. Conclusion: This study contributes to our understanding of the characteristics of disulfidptosis- related subgroups in BLCA. Disulfidptosis-related signatures can be used to assess the prognosis and immunotherapy of patients with BLCA.