ObjectiveThrough analyzing the SH2D5 expression profiles, clinical features, and immune infiltration in lung adenocarcinoma (LUAD), the study was intended to discuss the correlations of SH2D5 with prognosis and immune infiltration in LUAD.MethodsWe downloaded transcriptome and clinical data of LUAD patients from TCGA, GEO, and CCLE databases. Sangerbox, R language, GEPIA, UALCAN, and Kaplan-Meier Plotter were adopted to analyze the SH2D5 expression patterns, prognosis, and clinical features. Spearman correlation analysis was performed to determine the association between SH2D5 expression and immune cell infiltration and immune checkpoint genes. The miRNA-SH2D5 relations were predicted by miRDB and starbase. Lastly, quantitative PCR, IHC and Western blot were implemented for validation.ResultsA prominent up-regulation of SH2D5 was noted in the LUAD group relative to the normal group, which was validated by quantitative PCR, IHC and Western blot. SH2D5 expression was inversely related to overall survival (OS) of LUAD patients as well as B cell immune infiltration. Additionally, SH2D5 expression was negatively correlated with dendritic cells resting (p< 0.001), plasma cells (p< 0.001), mast cells resting (p= 0.031) and T cells CD4 memory resting (p= 0.036) in LUAD patients with abundant SH2D5 expression correlated with poor prognosis. Furthermore, enrichment analysis suggested that SH2D5 was associated with lung cancer and immunity. Lastly, we investigated the relationship between the expression of SH2D5 and the use of antitumor drugs.ConclusionHigh SH2D5 expression shares an association with unfavorable prognosis in LUAD, and SH2D5 may also provide new ideas for immunotherapy as a potential therapeutic target.