Abstract: We combined single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without neoadjuvant chemotherapy (NAC), whereas CDH12-enriched tumors have a superior response to immune checkpoint therapy (ICT). Patient stratification by tumor CDH12 enrichment offered better prediction outcome than established bladder cancer subtypes. The CDH12 population resembles an undifferentiated state with chemoresistance. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), likely explaining ICT efficacy in these tumors.