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Objective To investigate the correlation between ADAP2 gene and immune infiltration in tumor microenvironment in lung squamous cell carcinoma (LUSC), and to explore the prognostic values of ADAP2 in patients with LUSC. Methods The clinical information of patients with LUSC as well as the data of ADAP2 mRNA levels in cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. The association between ADAP2 gene and prognosis of patients was subsequently analyzed using Kaplan-Meier survival curve and Cox risk model analyses. xCell database was adopted to analyze the correlation of ADAP2 expression with immune infiltration in tumor microenvironment. Immunofluorescence double-staining test was employed to observe the co-localization of ADAP2 protein and CD163 (a specific biomarker of M2 macrophage). Results Multivariate Cox analysis showed that the expression of ADAP2 was an independent prognostic factor for LUSC patients, and its high expression was closely associated with the poor prognosis of patients (HR=1.533, 95%CI: 1.139~2.064, P=0.005). xCell analysis indicated that ADAP2 gene was positively correlated with both the tumor microenvironment score (r=0.609, 95%CI: 0.550~0.661, P < 0.001), and the immune infiltration score (r=0.596, 95%CI: 0.536~0.650, P < 0.001), and the expression of ADAP2 also showed a high positive association with mononuclear phagocyte system (macrophage, macrophage M1, macrophage M2 and monocyte) in LUSC (r=0.737, 0.718, 0.603 and 0.631, respectively, P < 0.001). Moreover, ADAP2 presented co-localization with CD163 and was mainly expressed in the cell membrane. Conclusion ADAP2 can act as a potential biomarker for predicting prognosis and evaluating the efficacy of immunotherapy in LUSC.