Objective To investigate the function of tumor necrosis factor α-induced protein 2 (TNFAIP2) in acute myeloid leukemia (AML) and its regulatory effect on immune function. Methods Blood samples were collected from 130 newly diagnosed AML patients admitted to the Hematology department of Xi'an International Medical Center Hospital from January 2021 to December 2022 and 100 healthy patients who underwent physical examination during the same period. The relative expression of TNFAIP2 mRNA in the blood of patients with AML were detected by RT-qPCR, and the correlation between clinicopathological features and AML was analyzed. The expression level of TNFAIP2 in AML and normal samples, the correlation between TNFAIP2 expression and immune checkpoint genes, and the survivability analysis were analyzed by GEPIA database. AML cell line MV4-11 was divided into control group, sh-NC group, sh-TNFAIP2 group (TNFAIP2 silent expression), LV-NC group and LV-TNFAIP2 group (TNFAIP2 overexpression). The expression levels of TNFAIP2 mRNA and protein in the cells were detected by RT-qPCR and Western blot, cell proliferation was detected by CCK-8 method, and apoptosis was detected by flow cytometry. MV4-11 cells and NK cells in each group were co-cultured, the killing activity of NK cells on MV4-11 cells was detected by LDH experiment, and the degranulation level of NK cells was detected by flow cytometry. Results Compared with healthy subjects, TNFAIP2 mRNA and protein expression levels were increased in AML patients (P＜0.05), the expression of TNFAIP2 was correlated with FAB classification and IDH1, CEBPA, TP53, RUNX1 mutations. NK cells and CD4+T/CD8+T ratio were decreased in patients with high expression of TNFAIP2 (P＜0.001), and CD8+T cell level was increased (P＜0.001). The GEPIA database analysis result showed that the AML tumor samples had high expression of TNFAIP2, and the survival of patients with low expression of TNFAIP2 was significantly longer than that of patients with high expression of TNFAIP2 (P=0.02). The expression level of TNFAIP2 was positively correlated with immune checkpoints CD27, CD86, CD276, CTLA4 (CD152), NRP1 (CD304), TIM3 (CD366), TNFRSF9 (CD137), ADORA2A and GITRL, and it was negatively correlated with PVRL2 (CD112), ICOSLG (CD275) and TMIGD2. Compared with control group and sh-NC group, the apoptosis level, NK cell killing activity and CD107a expression level in sh-TNFAIP2 group were increased (P＜0.05), while the relative cell activity and TNFAIP2 mRNA and protein levels in cells were decreased (P＜0.05). Compared with the control group and the LV-NC group, the apoptosis level, NK cell killing activity and CD107a expression level in the LV-TNFAIP2 group were decreased (P＜0.05), while the relative cell activity and TNFAIP2 mRNA and protein levels in the cells were increased (P＜0.05). Conclusion TNFAIP2 is highly expressed in AML and is closely related to the regulation of immune function. Overexpression of TNFAIP2 in MV4-11 cells can inhibit the cytotoxicity of NK cells