In immunocompetent mouse models, targeting EPHB2 with rAAV-8-shEPHB2 (EPHB2 inhibitor) inhibited HCC tumor growth and sensitized HCC cells to sorafenib (Leung et al., 2021), indicating that targeting tumor cell stemness may be a feasible therapeutic strategy against sorafenib resistance in HCC (Figure 1). This evidence concerns the gene EPHB2 and hepatocellular carcinoma.