Study On Effect And Mechanism Of High-dose Vitamin C Combined With Immune Checkpoint Inhibitor In Treating Liver Cancer

Background and Objective:Currently,the treatment of malignant tumors has entered the era of immunotherapy.Hepatocellular carcinoma(HCC)is the third most common cause of cancer-related death worldwide.Although immune checkpoint inhibitors(anti-PD-1/PD-L1)have benefited some HCC patients,only about 15-20% of HCC patients can benefit from anti-PD-1/PD-L1 antibody.The huge challenge facing immunotherapy for liver cancer is to solve the problem of ineffectiveness and resistance of immune checkpoint inhibitors in most HCC patients.The combination of immune checkpoint inhibitors(anti-PD-1/PD-L1)and other cancer therapies is an important measure to improve the efficacy of cancer immunotherapy.In recent years,many studies have found that the anti-angiogenic therapy-induced vascular normalization can not only reverse the neovascularization of tumor internal structures and functions,but also alleviate the interstitial high pressure,hypoxia and acidosis of the tumor microenvironment.Improving tissue perfusion and T-cell infusion to tumors can also relieve the state of immunosuppression,thereby enhancing the effect on immunotherapy.High-dose vitamin C(also known as L-ascorbic acid or ascorbate)has a significant effect on a variety of tumors,including HCC,and several clinical trials have confirmed that intravenous injection of high doses of vitamin C do have benefit on different cancers.Therefore,high-dose vitamin C may become a new strategy for the treatment of liver cancer,which is cheap,efficient,and low side effects.More and more studies show that vitamin C can affect the inflammatory response and the function of immune cells,which suggests that vitamin C may have a synergistic effect with immunotherapy,but the therapeutic effects and specific mechanisms need to be further studied.Results:1.High-dose vitamin C can promote the expression of PD-L1 in vivo and in vitro and enhance the efficacy of anti-PD-L1 antibody;2.High-dose vitamin C transforms HCC into "hot" tumors and its enhanced antiPD-L1 antibody efficacy depends on CD8+T cells;3.High-dose vitamin C activates cyclic GMP-AMP synthase(c GAS)in hepatoma cells and promotes the secretion of its product c GAMP4.c GAMP secreted by hepatoma cells activates the stimulator of interferon gene(STING)pathway of vascular endothelial cells,resulting in normalization of tumor vessels;5.The expression of c GAS and endothelial cell STING in HCC clinical samples was positively correlated with the infiltration of CD8+T cells;6.STING inhibitor abrogates the combinational efficiency of high-dose vitamin C and anti-PD-L1 therapy.Conclusion:High-dose vitamin C can increase the infiltration of CD8+T cells in liver cancers,transforms liver cancers into a "hot" tumor,thereby improving the therapeutic effect of immune checkpoint inhibitors(anti-PD-L1 antibodies).In terms of mechanism,high-dose vitamin C activates c GAS of hepatocellular carcinoma cells,promotes the secretion of its product c GAMP,and then activates the STING pathway of vascular endothelial cells,resulting in normalization of tumor blood vessels and eventually increase T cell infiltration.This study confirms the synergistic effect of high-dose vitamin C combined with immune checkpoint inhibitors in the treatment of liver cancer,and provides a more effective new strategy for clinical liver cancer treatment.