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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.