Low-Dose Carboplatin Reprograms Tumor Immune Microenvironment Through STING Signaling Pathway And Synergizes With PD-1 Inhibitors In Lung Cancer

Background and objective: At present,lung cancer is one of the most common malignant tumors in the world and even in China in terms of morbidity and mortality,among which non-small cell lung cancer accounts for three quarters.In recent years,surgical resection,chemoradiotherapy,immune drugs and other means have made rapid progress.In particular,the combination of chemotherapy and immunotherapy has become an emerging hot topic in the treatment of lung cancer,and has also become the focus of lung cancer research,but the possible mechanism of its synergistic effect is still unclear.In addition,safety has always been a major concern for clinicians when administering combination drugs to patients.Therefore,it is very important to determine the safe and effective dose of chemotherapy and the optimal chemotherapy period,so as to achieve the best effect of combined immunotherapy and to explore the specific mechanism of its synergistic effect.This study will analyze the effect of carboplatin on lung cancer cells;Further,in vivo experiments were conducted to study the changes of the immune environment in mice after carboplatin treatment,and to explore the possible molecular mechanism of carboplatin and PD-1 combined therapy,so as to provide a basis for improving the efficacy of immunotherapy and reducing the adverse reactions of combined therapy.Materials and methods: RNA sequencing,q PCR,Western blotting,flow cytometry,immunohistochemistry and immunofluorescence were used to observe the immunomodulatory effects of carboplatin treatment in mouse models.The safety of low-dose carboplatin was evaluated by MTT assay,weight change rate,blood routine test,liver and kidney function test and HE staining of small intestine and colon tissue structure.RNA interference and STING knockout mice were used to verify the role of STING in anti-tumor immune response.Result : We found that low dose carboplatin can induce DNA damage and simultaneously activate the classical STING-TBK1-IRF3 pathway and non-classical STING-NF-κB signaling pathway to exert immune stimulation.In addition,low-dose carboplatin transformed "cold" tumors into "hot" tumors through the hub of the STING pathway,which increased CD8+T cell infiltration and significantly increased PD-L1 expression,thus enhancing the anti-tumor benefits of PD-1 inhibitors.There were no obvious adverse reactions.In addition,after we knocked out STING in tumor cells,the up-regulation of PD-L1 and activation of STING pathway could be effectively reversed,and the anti-tumor effects of low-dose carboplatin and combination of carboplatin-PD-1 inhibitor were weakened.Conclusions: The results of our study showed that low dose carboplatin can activate STING signaling pathway,and then increase the expression of PD-L1 and the infiltration of CD8+T cells.This study revealed the immunomodulatory effect of low dose carboplatin,providing an economical,useful and safe choice for improving the efficacy of PD-1 inhibitor in lung cancer.