Currently, nivolumab (anti-PD-1) monotherapy, nivolumab plus ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), ramucirumab (anti-VEGF-R2), cabozantinib (mTKI), and regorafenib (mTKI) monotherapy are approved by the FDA as second-line therapy for unresectable HCC following the results of several clinical trials [28,29,30,31,32,33]. This evidence concerns the gene CTLA4 and hepatocellular carcinoma.