Multicenter retrospective study of prognostic impact of proliferative ecotype in urothelial carcinoma

Ki-67 is routinely used in clinical practice to quantify proliferative activity, yet proliferation has not been incorporated into current molecular classification systems for urothelial carcinoma (UC). A multicenter retrospective study in China investigated the tumor microenvironment (TME), therapeutic vulnerabilities, and clinical implications of the proliferative ecotype in US. The study included 1431 UC patients from four institutional cohorts and five publicly available datasets with comprehensive clinicopathological annotations. High Ki-67 expression identified a proliferative ecotype associated with markedly worse prognosis but enhanced sensitivity to platinum-based chemotherapy and PD-1/PD-L1 blockade. This ecotype displayed elevated tumor purity and tumor mutation burden, with characteristic genomic alterations including enrichment of TP53, ERCC2, and ATM/RB1/FANCC mutations and reduced 9p21.3 loss. The proliferative ecotype orchestrated an immune-enriched TME dominated by CD8⁺ T cells and B cells. Functional analyses revealed that CD8⁺ T cells preferentially differentiated toward an exhausted state, and mechanistic interrogation identified GDF15-TGFBR2 signaling axis through which epithelial cells modulated CD8⁺ T-cell dysfunction. The authors conclude that this study identifies a proliferative ecotype of UC with adverse prognosis and responsiveness to chemotherapy and immunotherapy.