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Unveiling Immune Metabolic Mechanisms in Bladder Cancer: Spatial Profiling Identifies ZFP36 as a Therapeutic Target

ABSTRACT: Treatment of bladder cancer (BLCA) is currently facing formidable challenges due to its high heterogeneity and immune evasion. In this study, we utilize spatial metabolomics (SM) and spatial transcriptomics (ST) to systematically analyze and visualize metabolic and transcriptional landscapes of BLCA. Correlation analysis reveals significant metabolic and transcriptional differences among tumor regions, shedding light on the heterogeneity and immune-related metabolic reprogramming mechanisms in BLCA. Further studies identify ZFP36 as a potential immunotherapeutic marker, with its higher expression correlating with poor prognosis in BLCA patients. Mechanistically, ZFP36 mediates the mRNA decay of key immune regulatory genes, including C1QBP, thereby suppressing T-cell activation and cytotoxicity. Notably, the combination of ZFP36 knockout and anti-PD-1 therapy demonstrated synergistic antitumor effects, suggesting that targeting ZFP36 may offer a promising therapeutic strategy for BLCA treatment. In summary, this study, through integrated multi-omics analysis, unveils the immune metabolic regulatory mechanisms of BLCA and provides crucial molecular targets for immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285715 | GEO | 2025/07/09

REPOSITORIES: GEO

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Unveiling Immune Metabolic Mechanisms in Bladder Cancer: Spatial Profiling Identifies ZFP36 as a Therapeutic Target

Project description:Unveiling Immune Metabolic Mechanisms in Bladder Cancer: Spatial Profiling Identifies ZFP36 as a Therapeutic Target

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Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [Affymetrix]

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ZFP36 RNA binding proteins restrain T-cell activation and anti-viral immunity [HITS-CLIP]

Project description:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which confirmed regulation of cytokine expression and revealed unanticipated actions in regulating T-cell activation and proliferation. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, most robustly through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis in a cell autonomous manner. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute viral infection, and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.

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ZFP36 RNA binding proteins restrain T-cell activation kinetics and anti-viral immunity [ribo-seq]

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ZFP36 RNA binding proteins restrain T-cell activation kinetics and anti-viral immunity [RNA-seq]

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Global Target mRNA Specification and Regulation by RNA-Binding Protein ZFP36/Tristetraprolin/TTP [Affymetrix]

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2013-12-24 | GSE53184 | GEO

Deletion of Smooth Muscle ZFP36 Promotes Neointimal Hyperplasia in Mice

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Project description:This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMGCR inhibitors, specifically simvastatin, are significantly associated with a reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several associated pathways. Higher levels of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and VLDL cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA. Meanwhile, RhoB is a key protein involved in the regulation of bladder cancer cell metastasis by simvastatin. Therefore, we tested the changes of key genes in bladder cancer cells after simvastatin (HMGCR inhibitor) treatment and overexpression of RhoB, respectively, using RNA sequencing.

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