Targeting androgen receptor transcriptionally represses VCP and enhances the efficacy of oncolytic-immunotherapy in hepatocellular carcinoma.

The immunoregulatory role of androgen receptor (AR) in hepatocellular carcinoma (HCC) is still poorly understood. Herein, we found that inhibition of AR function could induce immunogenic cell death (ICD) and trigger endoplasmic reticulum (ER) stress in vitro. Mechanistically, AR transcriptionally regulated the valosin-containing protein (VCP) expression via directly binding the promoter of VCP. AR inhibitor promoted dendritic cells (DCs) maturation in vitro and increased tumor-infiltrating DCs and CD8+ T cells in vivo. Combination of AR inhibitor with anti-PD-1 therapy remodels tumor immune microenvironment (TIME) and reduces tumor growth in mouse models of HCC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating VCP expression by AR and suggests that inhibition of AR has the potential to increase the efficacy of immunotherapy in HCC.