Interferon-a 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 interferon alpha (IFN-a) and anti-PD-1-based immunotherapy resulted in enhanced antitumor activity in unresectable HCC patients. In both immunocompetent orthotopic and spontaneous HCC models, IFN-a therapy synergized with anti-PD-1 and the combination treatment led to significant enrichment of cytotoxic CD27+ CD8+ T cells. Mechanistically, IFN-a suppressed HIF1a signaling by inhibiting FosB transcription in HCC cells, resulting in reduced glucose consumption capacity and consequentially establishing the 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-a reprograms glucose metabolism within HCC tumor microenvironment, thereby liberating T cell cytotoxic capacities and potentiating the PD-1 blockade-induced immune response. Our findings suggest that IFN-a and anti-PD-1 cotreatment is an effective novel combination strategy for HCC patients.