Objective To investigate the expression of TNFAIP8L2 gene in lung adenocarcinoma (LUAD), its correlation with clinical characteristics, and its functional role as a potential tumor suppressor using a combination of bioinformatics approaches and in vitro experiments. MethodsThe differential expression of TNFAIP8L2 between LUAD tissues and normal lung tissues were analyzed using UALCAN and TIMER databases, followed by further association analyses to elucidate the relationship between TNFAIP8L2 expression and clinical features in LUAD patients. Forty-eight pairs of LUAD and adjacent normal lung tissue samples were collected and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) to validate the expression level of TNFAIP8L2. In vitro, the effects of TNFAIP8L2 overexpression on proliferation and metastasis were assessed using CCK8 and transwell assays in A549 cells. The GEPIA and TIMER databases were utilized to explore the correlation between TNFAIP8L2 expression and patient prognosis. Moreover, STRING, cBioportal, and TISIDB databases were consulted to delve into potential protein-protein interactions involving TNFAIP8L2, its mutational status, and its relevance to immune cell infiltration within the tumor microenvironment of LUAD. ResultsTNFAIP8L2 expression was significantly lower in LUAD tissues compared to normal lung tissues, and low TNFAIP8L2 expression was strongly associated with poorer prognosis in LUAD patients. In vitro experiments definitively demonstrated that increased expression of TNFAIP8L2 could effectively inhibit proliferation and migration of A549 cells. TNFAIP8L2 was found to potentially interact with specific proteins including TLR1, CASP8, RAC1, SASH3, ARHGAP9, GIMAP8, S1PR4, LST1, TES, and RGS18. Additionally, TNFAIP8L2 expression was correlated with the infiltration levels of immune cells, such as NK cells, CD4+ and CD8+ T lymphocytes and others. ConclusionTNFAIP8L2 displays a trend of low expression in LUAD, where its downregulation is indicative of an adverse prognosis. Overexpression of TNFAIP8L2 effectively suppresses the growth and metastasis of LUAD cells. TNFAIP8L2 emerges as a promising biomarker with potential applications in LUAD diagnosis, prognosis evaluation, and guiding the development of immunotherapeutic strategies.