YAP1 suppression inhibits autophagy and improves the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Anti-PD-1 immunotherapy is a promising treatment for hepatocellular carcinoma (HCC), but some patients with HCC do not experience clinical benefits. Autophagy promotes tumor progression and participates in drug resistance. Previous studies have revealed that suppressing the expression level of Yes-associated protein 1 (YAP1) improves anti-PD-1 therapy efficacy. Therefore, the relationship between YAP1 expression and autophagy activity during anti-PD-1 treatment was investigated in this study. A positive correlation was found between the expression level of YAP1 and LC3B by analyzing The Cancer Genome Atlas (TCGA), UALCAN databases, and HCC tissue microarray. Meanwhile, YAP1 expression and autophagy constituted positive feedback, in which YAP1 inhibition decreased the autophagy activity in liver tumor cells by hepatocyte-specific Yap1 knockout mice. Further, anti-PD-1 treatment increased autophagy and YAP1 expression levels in the cancer tissues from DEN/TCPOBOP-induced liver cancer mice. Finally, Yap1 knockout suppressed autophagy and improved anti-PD-1 therapy efficacy in hepatocyte-specific Yap1 knockout mice with liver tumors. These results suggested that YAP1 suppression was sensitized to anti-PD-1 treatment and inhibited autophagy activity in liver tumor cells. YAP1 is a promising target for improving the efficacy of anti-PD-1 immunotherapy in HCC.