膀胱癌（BLCA）是一种高度异质性的疾病，其特征为明显的组织学、分子学和临床特征，并且其肿瘤发生和进展需要肿瘤细胞的异常代谢重编程。然而，目前的研究还没有系统和全面地阐述膀胱癌的代谢异质性。我们搜索了UCSC XENA门户网站，获取TCGA队列中BLCA患者的表达谱和临床注释。总共从Kyoto基因和基因组百科全书（KEGG）数据库下载了1,640个与代谢相关的基因。然后，采用一致性聚类的方法，根据代谢相关基因的表达将BLCA患者分为两种代谢亚型。我们使用Kaplan-Meier分析来评估代谢亚型的预后价值。随后，比较两种代谢亚型之间的免疫相关特征，以描述其免疫差异。然后，我们应用Scissor算法将代谢表型与单细胞转录组数据集相互联系，以确定与代谢亚型和预后相关的生物标志物。最后，我们使用包括63个BLCA和16个癌旁样本的临床队列验证了这些生物标志物的预后价值和免疫相关性。将BLCA患者分为两种具有明显特征的异质性代谢相关亚型（MRS）：MRS1，无活跃的代谢特征但存在免疫浸润的微环境，以及MRS2，脂原性亚型，其脂代谢上调。这两种亚型具有不同的预后、分子亚型分布以及与治疗相关通路的激活。MRS1 BLCAs更倾向于免疫抑制，且免疫检查点表达上调，这表明MRS1患者对免疫治疗具有良好的治疗反应。根据Scissor算法的结果，我们发现S100A7同时在MRS1表型和MRS1肿瘤细胞中上调，并与免疫特征呈正相关。此外，在包括63个BLCA和16个癌旁样本的临床队列中，S100A7明显与不良预后和增强的PD-L1表达相关。S100A7高表达的代谢亚型识别了免疫抑制的肿瘤微环境，并预测了膀胱癌中对免疫治疗的良好治疗反应。该研究为膀胱癌的代谢异质性提供了新的预后和治疗价值的见解。© 2023. BioMed Central Ltd., part of Springer Nature.

Bladder cancer (BLCA) represents a highly heterogeneous disease characterized by distinct histological, molecular, and clinical features, whose tumorigenesis and progression require aberrant metabolic reprogramming of tumor cells. However, current studies have not expounded systematically and comprehensively on the metabolic heterogeneity of BLCA.The UCSC XENA portal was searched to obtain the expression profiles and clinical annotations of BLCA patients in the TCGA cohort. A total of 1,640 metabolic-related genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then, consensus clustering was performed to divide the BLCA patients into two metabolic subtypes according to the expression of metabolic-related genes. Kaplan-Meier analysis was used to measure the prognostic values of the metabolic subtypes. Subsequently, comparing the immune-related characteristics between the two metabolic subtypes to describe the immunological difference. Then, the Scissor algorithm was applied to link the metabolic phenotypes and single-cell transcriptome datasets to determine the biomarkers associated with metabolic subtypes and prognosis. Finally, the clinical cohort included 63 BLCA and 16 para-cancerous samples was used to validate the prognostic value and immunological correlation of the biomarker.BLCA patients were classified into two heterogeneous metabolic-related subtypes (MRSs) with distinct features: MRS1, the subtype with no active metabolic characteristics but an immune infiltration microenvironment; and MRS2, the lipogenic subtype with upregulated lipid metabolism. These two subtypes had distinct prognoses, molecular subtypes distributions, and activations of therapy-related pathways. MRS1 BLCAs preferred to be immuno-suppressive and up-regulated immune checkpoints expression, suggesting the well-therapeutic response of MRS1 patients to immunotherapy. Based on the Scissor algorithm, we found that S100A7 both specifically up-regulated in the MRS1 phenotype and MRS1-tumor cells, and positively correlated with immunological characteristics. In addition, in the clinical cohort included 63 BLCA and 16 para-cancerous samples, S100A7 was obviously associated with poor prognosis and enhanced PD-L1 expression.The metabolic subtype with S100A7 high expression recognizes the immuno-suppressive tumor microenvironment and predicts well therapeutic response of immunotherapy in BLCA. The study provides new insights into the prognostic and therapeutic value of metabolic heterogeneity in BLCA.© 2023. BioMed Central Ltd., part of Springer Nature.