Steroidogenesis is associated with bladder cancer progression via reprogramming the metabolic landscape of the tumor immune microenvironment.

Bladder cancer represents a common malignant neoplasm of the genitourinary system, featuring an elevated recurrence rate and unfavorable prognosis, whereas the intrinsic mechanisms driving its malignant progression have not yet been fully clarified. In this study, we integrated single-cell transcriptome data from GSE222315 (5 bladder cancer samples and 4 adjacent normal samples) with bulk transcriptome data from the TCGA-BLCA cohort (409 tumor samples and 19 control samples) to investigate the impact of steroid metabolism on bladder cancer progression and the tumor stemness. Single-cell RNA sequencing analysis showed that steroid metabolism pathway genes were up-regulated in cancer cells. Also, the eminent steroid metabolism group exhibited stronger intensity and a greater number of intercellular interactions relative to the cohort characterized by diminished steroid metabolic capacity; additionally, tumor cells with high steroid metabolism showed elevated expression of stemness-related genes and diminished immune activity. Validation using bulk transcriptome data demonstrated that the steroid metabolism pathway was the most significantly enriched metabolic pathway in tumor tissues, and its core upregulated genes were negatively correlated with immune cell infiltration. Built upon differentially expressed genes including ACTC1 and CST1, the developed prognostic model showed superior predictive capability, with AUC scores over 0.77. Meanwhile, genes such as C7, DES, MYH11, and OGN were determined to be associated with unfavorable prognostic profiles in patients. And high-risk patients with poor prognosis outcomes in the survival model highly expressed steroid related genes like DHCR and SQLE. In conclusion, steroid metabolic reprogramming can reshape the TIME and is associated with bladder cancer progression, and reversing aberrant steroid metabolism has the potential to serve as a novel therapeutic regimen for bladder cancer.