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Although immunotherapy has revolutionized treatment strategies for MIBC, immune evasion remains a major obstacle limiting therapeutic efficacy. In this study, the mitochondrial calcium uniporter regulatory subunit (MCUB) is investigated for its role in immune evasion in MIBC. Bulk RNA\u2010seq, scRNA\u2010seq, and proteomic analyses revealed a progressive upregulation of MCUB from normal to MIBC tissues, and strong positive correlations are uncovered between MCUB expression and both PD\u2010L1\/PD\u20101 signaling and poor outcomes. Spatial transcriptomics and clinical tissue staining confirmed spatial co\u2010localization of MCUB and PD\u2010L1. Functional experiments demonstrated that MCUB stabilized PD\u2010L1 protein by reducing its lysosomal degradation through inhibition of PRKN\u2010dependent mitophagy. Mechanistically, MCUB suppressed mitochondrial calcium uptake to reduce PRKN activation and physically interacted with the PRKN\u2010Arg51 residue to inhibit its function. In vivo, MCUB knockdown led to reduced tumor growth, enhanced CD8\u207a T cell infiltration, and improved response to anti\u2010PD\u20101 therapy. This study identified the MCUB\u2010PRKN\u2010PD\u2010L1 axis as a novel driver of immune evasion in MIBC and proposed that targeting the MCUB\u2010PRKN interaction may serve as a precise therapeutic strategy to overcome immune resistance with minimal toxicity to normal tissues.<\/jats:p>","DOI":"10.1002\/advs.202514764","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T09:58:26Z","timestamp":1762941506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MCUB Inhibits PRKN\u2010Dependent Mitophagic Degradation of PD\u2010L1 to Promote Immune Evasion in Bladder Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0060-9109","authenticated-orcid":false,"given":"Yuan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology Nanfang Hospital Southern Medical University  Guangzhou Guangdong 510515 P. R. 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