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

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. Validation of immunometabolic reprogramming in bladder cancer by association analysis of spatial transcriptomics and spatial metabolomics

膀胱癌（Bladder Cancer, BLCA）目前因其高度异质性与免疫逃逸特性，面临诸多严峻的治疗挑战。本研究利用空间代谢组学（Spatial Metabolomics, SM）与空间转录组学（Spatial Transcriptomics, ST），对膀胱癌的代谢与转录组全景进行系统性分析与可视化呈现。相关性分析结果显示，肿瘤区域间存在显著的代谢与转录组差异，为阐明膀胱癌的异质性及免疫相关代谢重编程机制提供了重要依据。后续研究证实ZFP36可作为潜在的免疫治疗标志物，其高表达与膀胱癌患者的不良预后显著相关。机制层面，ZFP36可介导包括C1QBP在内的关键免疫调控基因的mRNA降解，进而抑制T细胞活化与细胞毒性功能。值得注意的是，ZFP36敲除联合抗PD-1治疗展现出协同抗肿瘤效应，提示靶向ZFP36或可为膀胱癌治疗提供极具前景的治疗策略。综上，本研究通过整合多组学分析，揭示了膀胱癌的免疫代谢调控机制，并为免疫治疗提供了关键分子靶点；同时通过空间转录组学与空间代谢组学的关联分析，验证了膀胱癌中的免疫代谢重编程过程。