Taurine Metabolism Drives Immune Suppression and Immunotherapy Resistance in Bladder Cancer

Bladder cancer (BLCA) is among the most common malignancies worldwide, yet fewer than half of muscle-invasive patients survive five years, and immunotherapy benefits only 20–30% of solid tumor patients broadly. A key obstacle is the immunosuppressive tumor microenvironment (TME), shaped by metabolic reprogramming. Taurine metabolism has emerged as a particularly important axis: tumor cells overexpressing the taurine transporter SLC6A6 deplete taurine from CD8+ T cells, triggering endoplasmic reticulum stress, ATF4-driven PD-1/TIM3 upregulation, and T cell exhaustion. Understanding how taurine metabolic dysregulation orchestrates these effects at the cellular and spatial level is critical for developing better therapies.

This study integrated single-cell RNA sequencing (scRNA-seq) from the GSE222315 dataset, spatial transcriptomics from GSE171351, and bulk transcriptomic data from TCGA-BLCA. The Seurat and Harmony pipelines were used for cell clustering and batch correction, while Monocle 3 reconstructed differentiation trajectories. Taurine metabolic scores were computed per cell using five methods including ssGSEA, AUCell, and UCell. A patient-level taurine metabolic dysregulation index (TMs) was built via Lasso and multivariate Cox regression on the TCGA cohort, split 7:3 into training and validation sets. Immune infiltration was assessed with ESTIMATE and TIDE algorithms, and mechanistic validation used CAF-BLCA co-culture systems with FAAH knockdown.

ScRNA-seq profiling revealed that taurine metabolic scores were significantly perturbed across epithelial cells, fibroblasts, and macrophages in the BLCA TME. High-TMs cell clusters were enriched for Notch signaling and EGFR tyrosine kinase inhibitor resistance pathways. Spatial transcriptomics confirmed spatiotemporal heterogeneity in taurine metabolic gene expression across tumor tissue sections. At the patient level, high TMs independently predicted shorter overall survival, and the combination of high TMs with high tumor mutational burden (TMB) produced synergistic prognostic deterioration. High-TMs tumors showed enrichment of immunosuppressive compartments—including M2 macrophages and regulatory T cells—and elevated expression of immune checkpoint molecules. CellChat analyses revealed altered ligand-receptor communication networks between taurine-high epithelial cells and immune/stromal cells. In co-culture experiments, FAAH knockdown in cancer-associated fibroblasts attenuated BLCA cell viability, potentially through CCL15 secretion, linking stromal taurine metabolism to paracrine tumor support.

These findings establish taurine metabolic dysregulation as a mechanistic driver of immunosuppression and tumor progression in BLCA, not merely a bystander phenomenon. The TMs framework provides a clinically actionable tool for patient stratification and offers a rationale for combining taurine-targeting strategies with immune checkpoint inhibitors. The identification of FAAH in CAFs as a functional node adds a stromal dimension to taurine biology in cancer.

Important caveats include the predominantly computational and in vitro nature of the mechanistic validation; in vivo models and clinical cohorts are needed to confirm causality. The co-culture findings around FAAH and CCL15 require further mechanistic dissection. Additionally, the TMs model was derived from TCGA data, which may not fully represent the diversity of BLCA patient populations globally.