Abstract
Natural killer (NK) cells play a crucial role in the surveillance of malignant cells. The engagement of NK group 2 member D (NKG2D) receptor with its ligands on target cells represents a promising therapeutic strategy against cancers. Here, we report that parvifoline AA (PAA), a natural ent-kaurane diterpenoid, markedly stimulates the expression of NKG2D ligands on hepatocellular carcinoma (HCC) cells, considerably enhancing their recognition and lysis by NK cells. We determined that PAA covalently binds to the conserved cysteine site of peroxiredoxins I/II (Prxs-I/II) and inhibits their catalytic activity, subsequently activating the ROS/ERK axis and the immunogenicity of HCC toward NK cells. Robust tumor growth inhibition by PAA dependent on NK cell activation was detected in vivo. Our data suggest Prxs-I/II as a promising cancer immune therapeutic target and provide a compelling rationale for further development of the inhibitor PAA as a sensitizer agent for NK cell-mediated HCC immunotherapy.