UDP-glucuronate decarboxylase 1 promotes tumor immune evasion by accelerating KMT2D loss in hepatocellular carcinoma.

Immune checkpoint blockade (ICB) targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has shown promise in hepatocellular carcinoma (HCC), but clinical responses are often limited in durability. Identifying novel drivers of immune evasion is crucial for improving therapeutic strategies. We employed a multi-omics integrative framework to identify HCC-specific immune biomarkers. Functional roles were validated using in vitro and in vivo models, including UDP-glucuronate decarboxylase 1 (UXS1) knockout/overexpression, co-culture assays, and various mouse models. Molecular mechanisms were dissected using immunoprecipitation coupled with mass spectrometry, ubiquitination assays, chromatin immunoprecipitation, luciferase reporter assays, and single-cell RNA sequencing. We identified the glycosyltransferase UXS1 as a novel immune-related prognostic hub gene in HCC. UXS1 was upregulated due to copy number gain and MZF1-driven promoter hypomethylation. Functionally, UXS1 promoted HCC malignancy independently of its canonical enzymatic activity. Mechanistically, UXS1 interacted with the E3 ligase F-box and WD repeat domain-containing 7 (FBXW7) to promote histone-lysine N-methyltransferase 2D (KMT2D) ubiquitination and degradation. We further discovered that KMT2D, acting as a non-catalytic scaffold, recruited the transcriptional repressor CCAAT enhancer binding protein beta (CEBPB) to the PD-L1 promoter to maintain its repression. UXS1-mediated KMT2D degradation disrupted this complex, leading to CEBPB dissociation and consequent PD-L1 transcriptional derepression. In vivo, UXS1 suppressed CD8+ T-cell effector function. UXS1 knockout synergized with anti-PD-1 therapy, and in human HCC, high UXS1 correlated with low KMT2D, high PD-L1, and reduced CD8+ T-cell infiltration. This study defines a novel UXS1-KMT2D-CEBPB-PD-L1 signaling axis, revealing how UXS1 drives immune evasion in HCC via epigenetic reprogramming. Targeting this axis may represent a potential strategy to overcome immune resistance, warranting further clinical investigation.