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In this study, we construct a spatial atlas of MIBC by integrating spatial transcriptomics from 22 tumors with matched bulk RNA and whole-exome sequencing data. We identify a continuous, spatially organized luminal-to-basal axis within individual tumors that is associated with greater chromosomal instability and transcriptional plasticity. Luminal tumor cores are enriched for FGFR3 and NECTIN4, whereas basal-like states localize toward invasive margins and are associated with elevated EGFR signaling, epithelial\u2013mesenchymal transition, genomic instability, immune infiltration, and greater chemotherapy sensitivity. Spatial analyses further reveal lineage- and location-associated differences in tertiary lymphoid structure states. Pan-cohort analyses across more than 3,000 tumors confirm conserved FGFR3\u2013EGFR lineage exclusivity and associated immune programs. 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This study establishes a spatial framework linking luminal and basal lineage states to distinct immune phenotypes and therapeutic vulnerabilities, providing a foundation for biomarker development and more precise, spatially informed, lineage-guided treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-26-0099","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T13:02:11Z","timestamp":1778677331000},"page":"2037-2059","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Spatial Atlas of Muscle-Invasive Bladder Cancer Reveals Lineage-Specific Vulnerabilities and Immune 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