Metabolic‐associated signature and hub genes associated with immune microenvironment and prognosis in bladder cancer

Abstract The relationship between metabolism and immune microenvironment remains to be studied in bladder cancer (BCa). We aimed to construct a metabolic‐associated signature for prognostic prediction and investigate its relationship with the immune microenvironment in BCa. The RNA expression of metabolism associated genes was obtained from a combined data set including The Cancer Genome Atlas, GSE48075, and GSE13507 to divide BCa patients into different clusters. A metabolic‐associated signature was constructed using the differentially expressed genes between clusters in the combined data set and validated in the IMvigor210 trial and our center. The composition of tumor‐infiltrating immune cells (TIICs) was evaluated using the single‐sample Gene Set Variation Analysis. BCa patients in Cluster A or high‐risk level were associated with advanced clinicopathological features and poor survival outcomes. The percentage of high‐risk patients was significantly lower in patients responding to anti‐PD‐L1 treatment. Compared with low‐risk patients, the IC50 values of cisplatin and gemcitabine were significantly lower in high‐risk patients. Thiosulfate transferase (TST) and S100A16 were significantly associated with clinicopathological features and prognosis. Downregulation of TST promoted BCa cell invasion, migration, and epithelial‐to‐mesenchymal transition, which are inhibited by downregulation of S100A16. CD8 + T cells, neutrophils, and dendritic cells had higher infiltration in the TST low‐level and the S100A16 high‐level. Furthermore, loss of function TST and S100A16 significantly affected the expression of PD‐L1 and CD47. The metabolic‐associated signature can stratify BCa patients into distinct risk levels with different immunotherapeutic susceptibility and survival outcomes. Metabolism disorder promoted the dysregulation of immune microenvironment, thus contributing to immunosuppression.