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Standalone biomarkers offer limited predictive value, necessitating integrative approaches combining clinicopathological, laboratory, and molecular factors to enhance accuracy. This study aimed to evaluate clinical and molecular factors, including the real-life performance of PD-L1 IHC, to improve treatment outcome prediction in ICI-treated UC patients, ultimately developing a more precise therapy selection model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a retrospective, multicenter study on advanced or metastatic UC patients with available formalin-fixed, paraffin-embedded tumor samples who underwent ICI therapy (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009100). NanoString technology was used to analyze 770 immune-related genes and a 60-gene panel for molecular subtype classification. Identified genes were validated in the IMvigor210 dataset. Whole tissue PD-L1 expression was assessed using the Dako 22C3 antibody.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our findings show that PD-L1 IHC has limited predictive value for ICI response. However, among multigene molecular factors, the neuronal signature, MDA p53-like, and TCGA\u2013luminal-infiltrated subtypes were linked to improved OS. Additionally, we identified and validated five novel ICI-predictive genes (\n                      <jats:italic>PSMB10, HLA-E, IRF7, CXCL12,<\/jats:italic>\n                      and\n                      <jats:italic>C3<\/jats:italic>\n                      ), and by combining molecular and clinicopathological parameters, we developed a model with enhanced predictive value.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our real-life cohort analysis confirms the limitations of standalone biomarkers like PD-L1. We identified gene expression-based markers with strong prognostic and predictive value for ICI treatment outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00262-025-04224-8","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T13:11:04Z","timestamp":1762953064000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Combining molecular patterns and clinical data for better immune checkpoint inhibitor prediction in metastatic urothelial carcinoma"],"prefix":"10.1007","volume":"74","author":[{"given":"M.","family":"V\u00e1radi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O.","family":"Horv\u00e1th","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"So\u00f3s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Csizmarik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"N\u00e9meth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"Gy\u0151rffy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Kenessey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Reis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Koll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Ol\u00e1h","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"Hadaschik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U.","family":"Krafft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Gr\u00fcnwald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Mairinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Wessolly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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G\u00fcnter Niegisch reports honoraria for lectures, symposia from Roche Pharma, MEDAC, Pfizer, BMS, AstraZeneca, and has had advisory roles for Roche Pharma, Sanofi, BMS, Merck Serono, Pfizer, MEDAC, Ipsen, Janssen; and reports support for travel expenses, congress fees from Roche Pharma, Pfizer, Merck, AstraZeneca. Viktor Gr\u00fcnwald has had advisory roles for Bristol Myers Squibb, Pfizer, MSD Oncology, Merck HealthCare, Ipsen, Eisai, Debiopharm, PCI Biotech, Cureteq, Oncorena and has received compensation for travel from Pfizer, Ipsen, Merck HealthCare, and reports honoraria from Bristol Myers Squibb, Pfizer, Ipsen, Eisai, MSD Oncology, Merck HealthCare, EUSAPHARM, APOGEPHA, Ono Pharmaceutical. Ulrich Krafft has received research funding from Bristol Myers Sqibb, Novartis\/AAA, and has received compensation for travel from Janssen Research funding, Bristol Myers Sqibb, Novartis\/AAA. Camilla M. Grunewald has had advisory roles for Ferring. The remaining authors have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"The study conformed to the Declaration of Helsinki and the institutional ethics committees approved the study protocol (SE RKEB 125\/2019, ETT-TUKEB BM\/13011-3\/2024\/EKU, 15\u20136400-BO, 2021\u20131548). Given the retrospective nature of the study, patient consent was waived.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All authors have read and approved the final manuscript for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"370"}}