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This work studies the tumor microenvironment (TME), therapeutic vulnerabilities, and clinical implications of the proliferative ecotype in UC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The authors assembled a multi\u2010cohort data set of 1431 UC patients from four institutional cohorts and five publicly available data sets with comprehensive clinicopathological annotations. Through an integrated multi\u2010omics framework coupled with experimental validation, they assessed how proliferative status shape\u00a0lineage differentiation, clinical outcomes, treatment response, and TME architecture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      High Ki\u201067 expression identified a proliferative ecotype associated with markedly worse prognosis but enhanced sensitivity to platinum\u2010based chemotherapy and PD\u20101\/PD\u2010L1 blockade. This ecotype displayed elevated tumor purity and tumor mutation burden, with characteristic genomic alterations including enrichment of\n                      <jats:italic>TP53<\/jats:italic>\n                      ,\n                      <jats:italic>ERCC2<\/jats:italic>\n                      , and\n                      <jats:italic>ATM\/RB1\/FANCC<\/jats:italic>\n                      mutations and reduced 9p21.3 loss. The proliferative ecotype orchestrated an immune\u2010enriched TME dominated by CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and B cells. Functional analyses revealed that CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells preferentially differentiated toward an exhausted state, and mechanistic interrogation identified a\n                      <jats:italic>GDF\u201015\u2013TGFBR2<\/jats:italic>\n                      signaling axis through which epithelial cells modulate CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cell dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identifies a proliferative ecotype of UC that is orthogonal to classical luminal\/basal ecotypes. Despite its adverse prognosis, this ecotype confers superior responsiveness to chemotherapy and immunotherapy and features a distinct genomic and immune ecosystem. These findings position proliferative status as a clinically actionable axis that may refine molecular classification and guide precision therapy in UC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.70515","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T09:31:24Z","timestamp":1782725484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proliferative ecotype determines lethal prognosis and\u00a0therapeutic benefit in urothelial carcinoma"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5409-3959","authenticated-orcid":false,"given":"Jiaxing","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Fudan University  Shanghai 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