Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. The gene discussed is TLR9; the disease is hepatocellular carcinoma.