Proliferative ecotype determines lethal prognosis and therapeutic benefit in urothelial carcinoma
Jiaxing Sun, Kaifeng Jin, Yawei Ding, Yuzhen Wu, Lingkai Zhang, Xiaohe Su, Jinming Shi, Zhaopei Liu, Han Zeng, Hailong Liu, Yuan Chang, Yu Zhu, Zewei Wang, Le Xu, Weijuan Zhang, Jiejie XuAbstract
Background
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). This work studies the tumor microenvironment (TME), therapeutic vulnerabilities, and clinical implications of the proliferative ecotype in UC.
Methods
The authors assembled a multi‐cohort data set of 1431 UC patients from four institutional cohorts and five publicly available data sets with comprehensive clinicopathological annotations. Through an integrated multi‐omics framework coupled with experimental validation, they assessed how proliferative status shape lineage differentiation, clinical outcomes, treatment response, and TME architecture.
Results
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 a GDF‐15–TGFBR2 signaling axis through which epithelial cells modulate CD8 + T‐cell dysfunction.
Conclusions
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.