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Here, we performed single\u2010cell transcriptome analysis from four patients with UC of the bladder (UCB), five patients with UC of the ureter (UCU), and four patients with UC of the renal pelvis (UCRP) to develop a comprehensive cell atlas of UC. We found the rare epithelial cell subtype EP9 with epithelial\u2010to\u2010mesenchymal transition (EMT) and cancer stem cell (CSC) features, and specifically expressed SOX6, which was associated with poor prognosis. We also found that ACKR1+ endothelial cells and inflammatory cancer\u2010associated fibroblasts (iCAFs) were more enriched in UCU, which may promote pathogenesis. While ESM1+ endothelial cells may more actively participate in UCB and UCRP tumorigenesis by promoting angiogenesis. Additionally, CD8 + effector T cells were more enriched in UCU and UCRP patients, while Tregs were mainly enriched in UCB tumors. C1QC+ macrophages and LAMP3+ dendritic cells were more enriched in UCB, which is closely related to the formation of the heterogeneous immunosuppressive microenvironment. Furthermore, we found strong interactions between iCAFs, EP9, and Endo_ESM1, and different degrees of activation of the FGF\u2010FGFR3 axis and immune checkpoint pathway were observed in different UC subtypes. Our study elucidated the cellular heterogeneity and the components of the microenvironment in UC arising from the upper and lower urinary tracts and provided novel therapeutic targets.<\/jats:p>","DOI":"10.1111\/cas.16436","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T07:59:46Z","timestamp":1735286386000},"page":"710-723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Single\u2010Cell RNA Sequencing Reveals the Tumor Heterogeneity and Immunosuppressive Microenvironment in Urothelial Carcinoma"],"prefix":"10.1111","volume":"116","author":[{"given":"Tianqi","family":"Lyu","sequence":"first","affiliation":[{"name":"Cixi Institute of Biomedical Engineering, Chinese Academy of Science (CAS) Ningbo Institute of Materials Technology and Engineering, CAS Ningbo  Ningbo 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(CAS) Ningbo Institute of Materials Technology and Engineering, CAS Ningbo  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaizhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Cixi Institute of Biomedical Engineering, Chinese Academy of Science (CAS) Ningbo Institute of Materials Technology and Engineering, CAS Ningbo  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Fu","sequence":"additional","affiliation":[{"name":"Cixi Institute of Biomedical Engineering, Chinese Academy of Science (CAS) Ningbo Institute of Materials Technology and Engineering, CAS Ningbo  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyao","family":"Wei","sequence":"additional","affiliation":[{"name":"Cixi Institute of Biomedical Engineering, Chinese Academy of Science (CAS) Ningbo Institute of Materials Technology and Engineering, CAS Ningbo  Ningbo 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