# Sphingolipid Metabolism Dysregulation Drives Immune Microenvironment Remodeling and Predicts Prognosis in Bladder Cancer

## TL;DR

This study shows that changes in sphingolipid metabolism in bladder cancer are linked to poor outcomes and immune system changes, offering new ways to predict prognosis and guide treatment.

## Contribution

A novel SMG-based prognostic signature was developed for bladder cancer with insights into immune microenvironment remodeling.

## Key findings

- Eight key sphingolipid metabolism-related genes were identified as prognostic markers in bladder cancer.
- High-risk patients showed increased immune activity, including higher infiltration of NK cells and CD8+ T cells.
- The risk model demonstrated strong prognostic performance with AUC values of 0.772 and 0.725 in training and validation cohorts.

## Abstract

The role of sphingolipid metabolism (SM) dysregulation in promoting bladder cancer (BLCA) progression and influencing patient prognosis has been well documented. To enhance therapeutic strategies, we aimed to identify key sphingolipid metabolism–related genes (SMGs) and develop a prognostic signature for personalized BLCA management. In this study, 430 BLCA samples from The Cancer Genome Atlas (TCGA) were analyzed via univariate Cox regression to screen critical SMGs involved in tumor progression. A LASSO regression model was applied to minimize overfitting, followed by multivariable Cox regression to construct and validate a SMG‐based prognostic signature in an independent cohort. Key findings revealed that SM dysregulation correlated with poor clinical outcomes and eight pivotal prognostic genes (ATP13A2, PCSK2, NR2F1, GSDMB, NFASC, NTF3, LGALS4, and SREBF1) were identified. The resulting risk model demonstrated robust prognostic performance with AUC values of 0.772 (training cohort) and 0.725 (validation cohort). Notably, high‐risk patients exhibited a highly active immunological profile characterized by elevated immune scores and enhanced functionality across 26 immune components, including increased infiltration of NK cells, CD8+ T cells, and elevated cytolytic activity. These results suggest that SM dysregulation may drive immunomodulatory changes in BLCA microenvironments, offering mechanistic insights into tumor immune evasion. This study provides a novel biomarker tool for risk stratification and highlights SM pathways as potential therapeutic targets for BLCA patients with immune microenvironment dysregulation.