Tumor-immune Co-evolution in hepatocellular carcinoma and itsimplication for immunotherapy resistance

1.Introduction In recent years,investigators have witnessed great progress in understanding the tumor microenvironment(TME)and evolution,which has been accompanied by a substantial number of newly developed targeted therapies and immunotherapies.Tumors are capable of escaping immune surveillance in the context of both spontaneous immune response and immunotherapies,and these two immune evasion processes share many overlapping mechanisms,such as human leukocyte antigen loss of heterozygosity(HLA-LOH)and immunoediting[1].For hepatocellular carcinoma(HCC),numerous treatment strategies targeting the TME have been proposed in recent years[2,3].Among these strategies,immune-checkpoint inhibitors(ICIs)have been found to be a promising therapeutic choice[4–6].The combination of atezolizumab(anti--programmed death-ligand 1,PD-L1)and bevacizumab(anti-vascular endothelial growth factor,VEGF)antibodies demonstrated significantly better overall and progression-free survival than the kinase inhibitor sorafenib in patients with unresectable HCC in a phase III trial[4],and this combination was established as a first-line treatment for advanced HCC.However,the response rate for ICIs was limited[4–6],and it was reported that nonalcoholic steatohepatitis-related HCC was less responsive to ICIs than other HCCs[7].Given the clinical importance of tolerance to immunotherapy in HCC,tumor-immune co-evolution deserves more attention and may provide novel ideas for developing new combination therapies that target multiple mechanisms of immunotherapy resistance.