〔Abstract〕 Objective To explore the regulation of the co-signaling molecule B7-H3 on the expression of interleukin 22(IL-22) and its clinical significance in lung adenocarcinoma. Methods CRISPR/Cas9 technology was used to knock out the B7-H3 gene of lung adenocarcinoma A549 cells(A549/KO), meanwhile, serum of 56 patients with lung adenocarcinoma was collected. Enzyme linked immunosorbent assay(ELISA) was used to detect the A549/KO culture supernatation and IL-22 level in serum of the patients and the content of soluble B7-H3(sB7-H3) in serum of the patients. The correlation between sB7-H3 and IL-22 was analyzed, the Logistic regression model was established to predict the risk factors of lung adenocarcinoma, and the value of sB7-H3 and IL-22 in the diagnosis of lung adenocarcinoma was discussed using receiver operating characteristic curve(ROC). Results The expression level of IL-22 in the supernatant of A549/KO cells was significantly lower than that of wild-type A549(P<0.05). The expression levels of sB7-H3 and IL-22 in the serum of patients with lung adenocarcinoma were significantly higher than those of healthy controls(P<0.05). The expression levels of sB7-H3 and IL-22 in the serum of patients with lung adenocarcinoma were related to pT stage, lymph node metastasis and pTNM stage(allP<0.05), and the expression levels of sB7-H3 and IL-22 were positively correlated(r s =0.316,P<0.05). sB7-H3(OR=1.423,95%CI: 1.139-1.778) and IL-22(OR=1.108,95%CI: 1.001-1.228) were selected as a predictors of lung adenocarcinoma through multivariate Logistic regression analysis. As a diagnostic indicator of lung adenocarcinoma. ROC curve analysis showed that the combined detection of IL-22 and sB7-H3(AUC=0.827,95%CI: 0.727-0.903) was better than the detection of sB7-H3 alone(AUC=0.795, 95%CI: 0.690-0.877) and IL-22 was tested alone(AUC=0.766, 95%CI: 0.658-0.853). Conclusion B7-H3 can play a role in the occurrence and development of lung adenocarcinoma by up-regulating IL-22 expression. Combined detection of serum sB7-H3 and IL-22 is helpful for the diagnosis and monitoring of lung adenocarcinoma.