In recent years, immune checkpoint inhibitor (ICI) in the treatment of unresectable liver cancer has attracted great attention in China and foreign countries and great progress has been achieved, but ICI monotherapy cannot bring benefits to most patients with liver cancer. Therefore, it is a new trend to explore the combination of ICI with other treatment methods. This article summarizes the advances in ICI combination therapy for unresectable liver cancer in China and foreign countries, including ICI combined with molecular targeted therapy, PD-1/PD-L1 inhibitor combined with CTLA-4 inhibitor, and ICI combined with local therapy. The results show that for patients with unresectable liver cancer, ICI combined with other treatment methods has a significantly better effect than ICI monotherapy; however, further studies are needed to explore which treatment method combined with ICI can bring the greatest benefits to patients.

The hypoxic microenvironment and inflammatory state of residual tumors caused by insufficient radio-frequency ablation(iRFA)are major reasons for rapid tumor progression and pose challenges for immu-notherapy.We retrospectively analyzed the clinical data of patients with hepatocellular carcinoma(HCC)treated with RFA and observed that iRFA was associated with poor survival outcomes and progression-free survival.Using an orthotopic HCC mouse model and a colorectal liver metastasis model,we observed that treatment with melatonin after iRFA reduced tumor growth and metastasis and achieved the best out-comes when combined with anti-programmed death-ligand 1(anti-PD-L1)therapy.In mechanism,melatonin inhibited the expression of epithelial-mesenchymal transitions,hypoxia-inducible factor(HIF)-1 α,and PD-L1 in tumor cells after iRFA.Flow cytometry revealed that melatonin reduced the proportion of myeloid-derived suppressor cells and increased the proportion of CD8+T cells.Transcriptomic analysis revealed an upregulation of immune-activated function-related genes in residual tumors.These findings demonstrated that melatonin can reverse hypoxia and iRFA-induced inflammation,thereby overcoming the immunosuppressive tumor microenvironment(TME)and enhancing the efficacy of immunotherapy.