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

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.

MCUB, mitophagy; PD‐L1; bladder cancer; immune evasion.