MCUB Inhibits PRKN‐Dependent Mitophagic Degradation of PD‐L1 to Promote Immune Evasion in Bladder Cancer

Abstract Muscle‐invasive bladder cancer (MIBC) poses a severe threat to patient survival due to its high invasiveness and metastatic potential. 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‐seq, scRNA‐seq, 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‐L1/PD‐1 signaling and poor outcomes. Spatial transcriptomics and clinical tissue staining confirmed spatial co‐localization of MCUB and PD‐L1. Functional experiments demonstrated that MCUB stabilized PD‐L1 protein by reducing its lysosomal degradation through inhibition of PRKN‐dependent mitophagy. Mechanistically, MCUB suppressed mitochondrial calcium uptake to reduce PRKN activation and physically interacted with the PRKN‐Arg51 residue to inhibit its function. In vivo, MCUB knockdown led to reduced tumor growth, enhanced CD8⁺ T cell infiltration, and improved response to anti‐PD‐1 therapy. This study identified the MCUB‐PRKN‐PD‐L1 axis as a novel driver of immune evasion in MIBC and proposed that targeting the MCUB‐PRKN interaction may serve as a precise therapeutic strategy to overcome immune resistance with minimal toxicity to normal tissues.