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

作者：Shuang Liu, Yihui Pan, Wenjian Liu, Xiaoyun Bu, Ruonan Shao, Qi Wang, Jun Wu, Chen Wu, Wenwei Hu, Jun Xu, Changping Wu, Jingting Jiang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012230 · 被引用次数：15 · 研究领域：Cancer Immunotherapy and Biomarkers、Hepatocellular Carcinoma Treatment and Prognosis、Immune cells in cancer

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ...