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Here, we integrated bulk, single\u2010cell, and spatial transcriptomic data with multiplexed immunofluorescence to construct a comprehensive cellular atlas across normal urothelium, precancerous lesions, and progressive BCa. We identified a stemness\u2010associated malignant epithelial population (Cluster 1_SDC1), a prognostically unfavorable subset of POSTN+ myofibroblastic cancer\u2010associated fibroblasts (mCAFs), and immunosuppressive monocytic myeloid\u2010derived suppressor cells (M\u2010MDSCs), all enriched in high\u2010grade tumors. Spatial mapping revealed a coordinated signaling cascade wherein POSTN+ mCAFs and M\u2010MDSCs co\u2010localize and engage integrin \u03b15\u03b21 on tip endothelial cells through FN1 and NAMPT, collectively driving angiogenesis. In turn, tip endothelial cells reinforce tumor stemness through downstream COL4A1\/2\u2013SDC1 signaling. Therapeutically, targeting integrin \u03b15\u03b21 with RGD peptide suppressed tumor growth and vascularization, while its combination with hydrogel\u2010based delivery and immune checkpoint blockade elicited broad\u2010spectrum antitumor responses. These findings uncover a spatially coordinated immune\u2013stroma\u2013tumor signaling cascade and establish integrin \u03b15\u03b21 as a central therapeutic target, providing a rationale for stroma\u2010directed combination strategies in progressive BCa.<\/jats:p>","DOI":"10.1002\/imo2.70102","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:16:36Z","timestamp":1782213396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrin \u03b15\u03b21\u2010mediated multicellular crosstalk in the tumor microenvironment drives bladder cancer progression and reveals targetable vulnerabilities"],"prefix":"10.1002","volume":"3","author":[{"given":"Ting","family":"Liang","sequence":"first","affiliation":[{"name":"College of Electronics and Information Engineering Shenzhen University Shenzhen 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