膀胱尿路上皮癌（UCB）是全球尿路系统中最常见的恶性肿瘤，尽管有多种治疗选择，但其复发率仍然显著。作为一种独特且新颖的铜依赖性编程细胞死亡机制，铜死亡在肿瘤免疫微环境、临床病理特征和患者预后方面的全面影响尚不清楚。 我们从TCGA和GEO下载的数据中，对568个UCB样本进行了全面的铜死亡模式检查，基于先前报道的10个与铜死亡有关的基因。然后，我们对不同模式之间差异的基因进行了单变量COX回归分析。使用主成分分析算法构建了一个铜死亡评分系统，以衡量个体铜死亡模式。为了验证评分系统，我们对具有不同病理分级的肿瘤组织进行了免疫组织化学染色，并对与预后相关的差异表达基因进行了体外实验。最后，我们使用IMvigor 210队列的数据验证了评分系统预测免疫治疗反应的能力。 通过研究，我们最终找到了四个独特的铜死亡簇和两个基因簇。各种铜死亡簇和基因簇之间的临床特征、预后状况、mRNA转录组、通路富集和免疫细胞浸润在肿瘤微环境中存在显著差异。为了确定UCB患者的个体铜死亡模式，我们还建立了一个铜死亡评分系统。多种方法的验证表明，该评分系统能够预测UCB患者的预后情况，并与TNM分类、肿瘤分级、分子类型和最终生存状态等临床特征有显著关联。结合病变突变负荷，可以有效预测UCB患者的临床结果。此外，我们发现铜死亡评分与对免疫治疗的应答和化疗的敏感性之间存在显著相关性。 本研究揭示了铜死亡对UCB肿瘤免疫微环境和临床病理特征的潜在影响。铜死亡评分系统能够有效预测患者的预后情况以及对化疗和免疫治疗的反应。版权所有 © 2023 Feng, Deng, Huang, Liu, Ruan, Wang and Liu.

Urothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear.A total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort.Four unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy.This study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.Copyright © 2023 Feng, Deng, Huang, Liu, Ruan, Wang and Liu.