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The contribution of tumor\u2010stromal crosstalk and macrophage recruitment to chemoresistance remains poorly understood. This study investigated these mechanisms using a functional\n                    <jats:italic>ex vivo<\/jats:italic>\n                    bladder cancer tissue slice model combined with\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200964 spatial transcriptomics. Spatial analysis revealed transcriptomic changes involving the immunomodulating gene\n                    <jats:italic>SPP1<\/jats:italic>\n                    that has been also recently presented as a putative predictive biomarker for neoadjuvant chemotherapy in bladder cancer. Moreover, Non\u2010Responders exhibited upregulation of chemokines including\n                    <jats:italic>CXCL1<\/jats:italic>\n                    and\n                    <jats:italic>CXCL8<\/jats:italic>\n                    and enrichment of immunoregulatory M2 macrophages in tumor regions, suggesting active macrophage recruitment from the stroma. On the contrary, Responders showed upregulation of complement components, proinflammatory macrophage subsets and signals associated with cytotoxic lymphocyte recruitment. Tissue slices corresponding cell cultures confirmed overexpression of immunomodulating markers including checkpoints\n                    <jats:italic>PD\u2010L1<\/jats:italic>\n                    and\n                    <jats:italic>PD\u2010L2<\/jats:italic>\n                    in Non\u2010Responder cancer cells upon Gem\/Cis treatment. Using TCGA bladder cancer data, the transcriptomic gene set was further validated revealing a prognostic signature associated with patients' outcome. These findings uncover a novel mechanism of chemotherapy resistance in bladder cancer driven by tumor\u2013stromal interactions and macrophage recruitment and suggest that targeting macrophage infiltration may improve chemotherapy response in bladder cancer.\n                  <\/jats:p>","DOI":"10.1002\/2211-5463.70179","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T05:38:57Z","timestamp":1765604337000},"page":"1197-1212","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tumor\u2010stromal crosstalk and macrophage enrichment are associated with chemotherapy response in bladder cancer"],"prefix":"10.1002","volume":"16","author":[{"given":"Sophie","family":"Leypold","sequence":"first","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen University  Germany"},{"name":"Center for Integrated Oncology (CIO) D\u00fcsseldorf CIO Aachen Bonn K\u00f6ln D\u00fcsseldorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0701-060X","authenticated-orcid":false,"given":"Janik","family":"Riese","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen University  Germany"},{"name":"Center for Integrated Oncology (CIO) D\u00fcsseldorf CIO Aachen Bonn K\u00f6ln D\u00fcsseldorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6704-2422","authenticated-orcid":false,"given":"Lancelot","family":"Seillier","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen University  Germany"},{"name":"Center for Integrated Oncology (CIO) D\u00fcsseldorf CIO Aachen Bonn K\u00f6ln D\u00fcsseldorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-2576","authenticated-orcid":false,"given":"Mark","family":"K\u00fchnel","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen University  Germany"},{"name":"Center for Integrated Oncology (CIO) D\u00fcsseldorf CIO Aachen Bonn K\u00f6ln D\u00fcsseldorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Pannhausen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen University  Germany"},{"name":"Center for Integrated Oncology (CIO) D\u00fcsseldorf CIO Aachen Bonn K\u00f6ln D\u00fcsseldorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte O. 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