IFNa Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment

The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFN alpha and anti-PD-1-based immu-notherapy resulted in enhanced antitumor activity in patients with unresectable HCC. In both immuno-competent orthotopic and spontaneous HCC models, IFN alpha therapy synergized with anti-PD-1 and the combination treatment led to signifi cant enrichment of cytotoxic CD27 +CD8+ T cells. Mechanistically, IFN alpha suppressed HIF1 alpha signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing a high-glucose microenvironment that fostered transcription of the T-cell costimulatory molecule Cd27 via mTOR-FOXM1 signaling in infiltrating CD8 + T cells. Together, these data reveal that IFN alpha reprograms glucose metabolism within the HCC tumor microenvironment, thereby liberating T-cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our fi ndings suggest that IFN alpha and anti-PD-1 cotreatment is an effective novel combination strategy for patients with HCC. SIGNIFICANCE: Our study supports a role of tumor glucose metabolism in IFN alpha-mediated antitumor immunity in HCC, and tumor-infi ltrating CD27 +CD8+ T cells may be a promising biomarker for stratifying patients for anti-PD-1 therapy.