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Proteins were extracted from formalin\u2010fixed, paraffin\u2010embedded samples and analyzed using data\u2010independent acquisition, yielding &gt;8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell\u2013cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid\/DNA metabolism. Treatment\u2010na\u00efve MIBC presents three proteomic subgroups with resemblance to the basal\u2010squamous, stroma\u2010rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune\u2010depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2\u2010like tumor\u2010associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP\u201014. Genomic panel sequencing yielded the prototypical profile of prevalent\n                    <jats:italic>FGRF3<\/jats:italic>\n                    alterations in NMIBC and\n                    <jats:italic>TP53<\/jats:italic>\n                    alterations in MIBC. Tumor\u2013stroma interactions of MIBC were investigated by proteomic analysis of patient\u2010derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor\u2010induced stromal proteome phenotypes. \u00a9 2024 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6367","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T04:04:52Z","timestamp":1732507492000},"page":"41-56","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Proteomic analysis of non\u2010muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment"],"prefix":"10.1002","volume":"265","author":[{"given":"Thien\u2010Ly Julia","family":"Dinh","sequence":"first","affiliation":[{"name":"Institute for Surgical Pathology, Faculty of Medicine, Medical Center\u2014University of Freiburg University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6658-9159","authenticated-orcid":false,"given":"Manuel","family":"Rogg","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Faculty of Medicine, Medical Center\u2014University of Freiburg University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-3229","authenticated-orcid":false,"given":"Miguel","family":"Cosenza\u2010Contreras","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Faculty of 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