Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer
BackgroundBladder cancer (BLCA) remains heavily dependent on bacillus Calmette-Guérin (BCG) therapy due to the profound heterogeneity of its tumor microenvironment (TME) and deregulated metabolic landscapes. Taurine metabolism (TM) is a pivotal axis in BLCA, exhibiting dual roles in tumor progressio...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618439/full |
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| author | Zhengfang Liang Fengwei Nong Fengwei Nong Zhenjie Li Runmin Chen Haoxu Zhao Yongping Huang Yongping Huang |
| author_facet | Zhengfang Liang Fengwei Nong Fengwei Nong Zhenjie Li Runmin Chen Haoxu Zhao Yongping Huang Yongping Huang |
| author_sort | Zhengfang Liang |
| collection | DOAJ |
| description | BackgroundBladder cancer (BLCA) remains heavily dependent on bacillus Calmette-Guérin (BCG) therapy due to the profound heterogeneity of its tumor microenvironment (TME) and deregulated metabolic landscapes. Taurine metabolism (TM) is a pivotal axis in BLCA, exhibiting dual roles in tumor progression and immune evasion. Deciphering the molecular mechanisms by which TM reprogramming fosters immunosuppression is imperative for advancing BLCA immunotherapy.MethodsThis study employed an integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk transcriptome analyses to unravel taurine metabolic dysregulation in the BLCA TME. Computational frameworks such as Seurat and Monocle 3 were used to characterize cellular subpopulations, reconstruct differentiation trajectories, and model intercellular signaling networks. A taurine metabolic dysregulation index (TMs) was developed using TCGA cohorts, with survival modeling and machine learning methodologies deployed to assess its prognostic utility. Immuno-infiltration patterns and immunotherapeutic responsiveness were quantified via algorithms including ESTIMATE and TIDE. Mechanistic validation was achieved through co-culture systems.ResultsScRNA-seq profiling revealed significant perturbations in TM scores across epithelial cells, fibroblasts, and macrophages within the BLCA TME. High TMs clusters were enriched for Notch signaling and EGFR tyrosine kinase inhibitor resistance pathways. Spatial transcriptomics analyses highlighted spatiotemporal heterogeneity in taurine metabolic gene expression. The TMs index emerged as an independent prognostic biomarker, with high TMs patients demonstrating significantly shorter overall survival and synergistic prognostic deterioration in the context of high tumor mutational burden (TMB). High TMs tumors exhibited enrichment of immunosuppressive cell compartments and elevated immune checkpoint molecule expression. Mechanistically, FAAH knockdown in cancer-associated fibroblasts (CAFs) attenuated co-cultured BLCA cell viability, potentially mediated by CCL15 secretion.ConclusionThis study establishes that taurine metabolic dysregulation reconfigures intercellular signaling within the BLCA TME, driving immunosuppression and tumor progression. The TMs framework enables robust patient stratification and provides a mechanistic rationale for therapeutic strategies targeting TM in conjunction with immune checkpoint inhibitors, thus paving the way for advanced precision medicine approaches in BLCA. |
| format | Article |
| id | doaj-art-3b18fc6acbe1420fa7d4e5698ab3602a |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-3b18fc6acbe1420fa7d4e5698ab3602a2025-08-20T02:21:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16184391618439Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancerZhengfang Liang0Fengwei Nong1Fengwei Nong2Zhenjie Li3Runmin Chen4Haoxu Zhao5Yongping Huang6Yongping Huang7Department of Urinary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaThe First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, ChinaDepartment of Renal Diseases, Affiliated Hospital of Youjiang Medical University for Nationalites, Baise, Guangxi, ChinaDepartment of Urinary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaDepartment of Urinary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaDepartment of Urinary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaDepartment of Urinary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaKey Laboratory of Tumor Molecular Pathology of Baise, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaBackgroundBladder cancer (BLCA) remains heavily dependent on bacillus Calmette-Guérin (BCG) therapy due to the profound heterogeneity of its tumor microenvironment (TME) and deregulated metabolic landscapes. Taurine metabolism (TM) is a pivotal axis in BLCA, exhibiting dual roles in tumor progression and immune evasion. Deciphering the molecular mechanisms by which TM reprogramming fosters immunosuppression is imperative for advancing BLCA immunotherapy.MethodsThis study employed an integrative approach combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and bulk transcriptome analyses to unravel taurine metabolic dysregulation in the BLCA TME. Computational frameworks such as Seurat and Monocle 3 were used to characterize cellular subpopulations, reconstruct differentiation trajectories, and model intercellular signaling networks. A taurine metabolic dysregulation index (TMs) was developed using TCGA cohorts, with survival modeling and machine learning methodologies deployed to assess its prognostic utility. Immuno-infiltration patterns and immunotherapeutic responsiveness were quantified via algorithms including ESTIMATE and TIDE. Mechanistic validation was achieved through co-culture systems.ResultsScRNA-seq profiling revealed significant perturbations in TM scores across epithelial cells, fibroblasts, and macrophages within the BLCA TME. High TMs clusters were enriched for Notch signaling and EGFR tyrosine kinase inhibitor resistance pathways. Spatial transcriptomics analyses highlighted spatiotemporal heterogeneity in taurine metabolic gene expression. The TMs index emerged as an independent prognostic biomarker, with high TMs patients demonstrating significantly shorter overall survival and synergistic prognostic deterioration in the context of high tumor mutational burden (TMB). High TMs tumors exhibited enrichment of immunosuppressive cell compartments and elevated immune checkpoint molecule expression. Mechanistically, FAAH knockdown in cancer-associated fibroblasts (CAFs) attenuated co-cultured BLCA cell viability, potentially mediated by CCL15 secretion.ConclusionThis study establishes that taurine metabolic dysregulation reconfigures intercellular signaling within the BLCA TME, driving immunosuppression and tumor progression. The TMs framework enables robust patient stratification and provides a mechanistic rationale for therapeutic strategies targeting TM in conjunction with immune checkpoint inhibitors, thus paving the way for advanced precision medicine approaches in BLCA.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618439/fullbladder cancerspatial transcriptomicstaurineCAFsanti-PD-1 |
| spellingShingle | Zhengfang Liang Fengwei Nong Fengwei Nong Zhenjie Li Runmin Chen Haoxu Zhao Yongping Huang Yongping Huang Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer Frontiers in Immunology bladder cancer spatial transcriptomics taurine CAFs anti-PD-1 |
| title | Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer |
| title_full | Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer |
| title_fullStr | Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer |
| title_full_unstemmed | Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer |
| title_short | Taurine-mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti-PD-1 resistance in bladder cancer |
| title_sort | taurine mediated metabolic immune crosstalk indicates and promotes immunosuppression with anti pd 1 resistance in bladder cancer |
| topic | bladder cancer spatial transcriptomics taurine CAFs anti-PD-1 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618439/full |
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