叶酸代谢对基因组稳定性的维持至关重要，由于在癌细胞中具有甲基化、核苷酸代谢和还原能力的调节作用。然而，叶酸代谢相关基因在尤其是膀胱癌（BLCA）中的预后价值尚不清楚。从公共数据库中检索到91个与叶酸代谢相关的基因。选择从癌症基因组图谱中获取的TCGA-BLCA队列进行训练，而从基因表达图谱数据库中下载的GSE13507、GSE31684和GSE32894以及从当地医院收集的35个BLCA样本用于外部验证。通过基因组差异检测、蛋白质相互作用网络分析、LASSO回归和Cox回归，构建了一个包括ATIC、INS和MTHFD1L的三基因标记。该标记在多个独立队列中是可靠的预后预测因子（合并风险比=2.79，95%置信区间=1.79-4.33）。该标记与BLCA的恶性程度有关，这在当地临床样本（P < 0.01）和多个细胞系中得到验证（所有P < 0.05）。此外，使用TIDE算法、GSE111636队列和IMvigor210队列表明该标记是评估免疫治疗反应的有希望的工具。综上所述，构建了一个与叶酸代谢相关的基因标记，用于预测BLCA的预后和免疫治疗敏感性，并在多个大规模队列、临床样本和细胞实验中进行了验证，为生物机制提供了新的见解。© 2023. 作者独家授权给Springer-Verlag GmbH Germany，Springer Nature的一部分。

Folate metabolism is critical for the maintenance of genomic stability due to its regulatory ability to methylation, nucleotide metabolism, and reduction capabilities in cancer cells. However, the prognostic value of folate metabolism-related genes has not been clarified, especially in bladder cancer (BLCA). 91 folate metabolism-related genes were retrieved from the public database. TCGA-BLCA cohort, obtained from the Cancer Genome Atlas, was selected for training, while GSE13507, GSE31684, and GSE32894, downloaded from the Gene Expression Omnibus, and 35 BLCA samples collected from the local hospital were used for external validation. Through genomic difference detection, protein-protein interaction network analysis, LASSO regression, and Cox regression, a three-gene signature, including ATIC, INS, and MTHFD1L, was constructed. The signature was a reliable prognosis predictor across multiple independent cohorts (pooled hazard ratio = 2.79, 95% confidence interval = 1.79-4.33). The signature was associated with the BLCA malignant degree, which was validated in the local clinical samples (P < 0.01) and multiple cell lines (all P < 0.05). Additionally, the TIDE algorithm, GSE111636 cohort, and IMvigor210 cohort indicated that the signature was a promising tool to evaluate the immunotherapeutic response. Collectively, a folate metabolism-related gene signature was constructed to predict the prognosis and immunotherapeutic sensitivity in BLCA, which was verified in multiple large-scale cohorts, clinical samples, and cellular experiments, providing novel insights into the biological mechanisms.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.