Hypoxia-related CircARSB Modulates lipid metabolism and innate immune crosstalk to influence immune checkpoint inhibitor response in hepatocellular carcinoma.

Intratumoral heterogeneity (ITH) in hepatocellular carcinoma (HCC), driven by malignant cells plasticity, underlies differential responses to immune checkpoint inhibitors (ICIs). Single-nucleus sequencing revealed that hypoxic stress regulated malignant cellular plasticity, promoting transitions from an innate immune-responsive state to a non-responsive state with elevated lipid metabolism and angiogenesis. Whole-transcriptome sequencing revealed CircARSB was upregulated in responders and indicated better prognosis under ICIs treatment. Mechanistically, under normoxia, CircARSB activated the type I interferon-mediated innate immune pathway, whereas under hypoxia, it underwent mA methylation and interacted with MOV10 to inhibit lipid metabolism. Exosomal CircARSB suppressed angiogenesis and facilitated ICI-responsive Kupffer cell subclusters. In vivo, under tyrosine kinase inhibitor (TKI)-alleviated hypoxia, adeno-associated virus (AAV)-delivered CircARSB remodeled the ICI-responsive tumor microenvironment by promoting CD8 T cell infiltration, M1 macrophage polarization, and IFN-β production. Clinically, an MRI-based radiomics model (Circ-DWI with HIF1A-ADC) was developed to guide personalized treatment ICIs, alone or in combination with TKIs or CircARSB. Collectively, hypoxia-related CircARSB emerges as a promising biomarker for therapeutic response stratification and a potential target to enhance the efficacy of ICIs-based therapy in HCC.