Lactylation-driven MVP upregulation boosts immunotherapy resistance by inhibiting PD-L1 degradation in hepatocellular...

Hepatocellular carcinoma (HCC) is a prevalent malignancy and the third leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as first-line therapies for advanced HCC, substantially improving clinical outcomes. However, resistance to ICIs remains a major therapeutic challenge. Lactylation, a recently identified post-translational modification, has been implicated in tumor progression, although its role in ICIs resistance in HCC remains unclear.

Cytotoxicity assays, flow cytometry and orthotopic HCC mouse model were used to evaluate the effects of lactylation in remodeling the immune microenvironment. Chromatin immunoprecipitation sequencing and RNA sequencing were employed to identify lactylation-regulated gene profiles. Programmed cell death-ligand 1 (PD-L1) protein degradation was assayed by cycloheximide-chase analysis and ubiquitination assay. Interactions between major vault protein (MVP) and β-transducin repeat-containing protein (β-TrCP) were analyzed by co-immunoprecipitation experiments. Site-directed mutagenesis and truncation mutants were designed to determine binding sites of MVP-β-TrCP complex.

Elevated lactylation correlates with poor prognosis and ICIs resistance in patients with HCC. Inhibition of lactylation enhances CD8⁺ T-cell infiltration and cytokine production. Multiomics analyses identify MVP as a lactylation-regulated factor that suppresses CD8⁺ T cell-mediated antitumor immunity. Elevated MVP expression is associated with resistance to checkpoint blockade therapy. Mechanistic studies reveal that histone lactylation-induced MVP upregulation stabilizes PD-L1 by preventing β-TrCP-mediated proteasomal degradation. Pharmacological inhibition of lactylation restores ICIs sensitivity in orthotopic HCC mouse models.

Our findings demonstrate that histone lactylation promotes ICIs resistance via MVP-dependent PD-L1 stabilization. Therefore, targeting lactylation in combination with programmed cell death protein-1/PD-L1 blockade offers a promising strategy to overcome immunotherapy resistance in HCC.