A Spatial Atlas of Muscle-Invasive Bladder Cancer Reveals Lineage-Specific Vulnerabilities and Immune Architecture

Here, we construct the first spatial atlas of MIBC by integrating spatial transcriptomics from 22 tumors with matched bulk RNA sequencing and whole-exome sequencing. We identify a continuous, spatially organized luminal-to-basal differentiation axis within each individual tumor, driven by progressive copy number alterations and transcriptional plasticity.

This axis delineates tumor compartments with opposing therapeutic vulnerabilities. Luminal tumor cores are enriched for FGFR3 and NECTIN4 expression, and heightened sensitivity to NECTIN4-directed antibody–drug conjugates. In contrast, basal-like tumor states localize to invasive margins, elevated EGFR signaling, epithelial–mesenchymal transition, genomic instability, immune infiltration, and increased chemosensitivity.