{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:32:47Z","timestamp":1790371967378,"version":"4.1.0"},"reference-count":79,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Urothelial carcinoma (UC) is a biologically and clinically heterogeneous disease arising from the bladder and upper urinary tract. Immune checkpoint inhibitors (ICIs) have transformed treatment of advanced UC, yet durable responses remain limited to a minority of patients, underscoring the need to better understand the tumor immune microenvironment (TME). This narrative review examines the UC immune phenotype across disease stages and anatomical sites, integrating evidence from bulk and single-cell transcriptomics, spatial profiling, and translational studies. We describe the principal immune cell populations of the UC TME\u2014including cytotoxic and regulatory T cells, macrophages, myeloid-derived suppressor cells, natural killer cells, B cells, and dendritic cells\u2014and their relationship to established molecular subtypes. We review how this immune landscape evolves from non-muscle-invasive to metastatic disease, including the distinct contexture of upper tract UC and variant histology. We critically evaluate established ICI biomarkers (PD-L1, FGFR3, tumor mutational burden, mismatch repair deficiency) alongside emerging candidates\u2014tumor-infiltrating lymphocyte density, HLA class I expression, tertiary lymphoid structures, and multiparameter transcriptomic scores\u2014noting that most remain investigational and require prospective validation before clinical use. Finally, we address key biological, technical, and clinical barriers to this research and outline future directions in AI-assisted digital pathology and multimodal biomarker integration. A comprehensive characterization of UC immune phenotype is essential to guide rational, biomarker-driven patient selection and optimize next-generation immunotherapy strategies.<\/jats:p>","DOI":"10.3390\/cancers18152392","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune Phenotype in Urothelial Carcinoma: From Tumor Biology to Therapeutic Stratification"],"prefix":"10.3390","volume":"18","author":[{"given":"Patricia","family":"Toquero","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"},{"name":"C\u00e1tedra UAM-Fundaci\u00f3n Instituto Roche de Medicina Personalizada de Precisi\u00f3n, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3427-2931","authenticated-orcid":false,"given":"Luis San","family":"Jos\u00e9","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"},{"name":"Department of Urology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantzazu","family":"Alfranca","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"},{"name":"Department of Immunology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Celada","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"},{"name":"Department of Urology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6793-820X","authenticated-orcid":false,"given":"Clara","family":"Velasco","sequence":"additional","affiliation":[{"name":"Department of Urology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laia","family":"Figols","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Prada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Gajate","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Pernaut","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario Severo Ochoa, 28914 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imanol","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6393-3444","authenticated-orcid":false,"given":"Ram\u00f3n","family":"Colomer","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"},{"name":"C\u00e1tedra UAM-Fundaci\u00f3n Instituto Roche de Medicina Personalizada de Precisi\u00f3n, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8715-8860","authenticated-orcid":false,"given":"Nuria","family":"Romero-Laorden","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Universitario de La Princesa, 28006 Madrid, Spain"},{"name":"C\u00e1tedra UAM-Fundaci\u00f3n Instituto Roche de Medicina Personalizada de Precisi\u00f3n, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Princesa [IIS-Princesa], 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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