<p>Lung adenocarcinoma (LUAD), the most common type of lung cancer, is a leading cause of cancer-related mortality. <i>NT5E</i>, an ecto-5’-nucleotidase enzyme, has been implicated in cancer progression, particularly in efferocytosis. Despite its potential involvement, the prognostic significance of <i>NT5E</i> and relationship with immune cell infiltration in LUAD have not been extensively explored. In this study, we performed a comprehensive analysis to elucidate the expression patterns of <i>NT5E</i> and its prognostic implications in LUAD using data from diverse public databases. Multiple computational algorithms, including CIBERSORT, ESTIMATE, and xCell, were employed to assess the correlation between <i>NT5E</i> expression and immune cell infiltration. We found that <i>NT5E</i> was significantly overexpressed at both the mRNA and protein levels in LUAD tissues. Elevated <i>NT5E</i> expression was significantly linked to multiple clinicopathological factors, including metastasis and pathological stage, and served as a strong predictor of poor prognosis in LUAD patients. Gene Set Enrichment Analysis (GSEA) indicated that <i>NT5E</i> plays a crucial role in regulating immune responses, as evidenced by differential gene expression associated with <i>NT5E</i> levels. A strong positive correlation was observed between <i>NT5E</i> expression and the presence of immune cells, including dendritic cells, macrophages, and CD4⁺ T cells, as well as the expression of various immune cell markers, suggesting that <i>NT5E</i> may influence the prognosis of LUAD patients by regulating immune cell infiltration. Additionally, drug sensitivity analysis highlights the potential of selumetinib and PD318088, both MEK1/2 inhibitors, to target NT5E in LUAD treatment, suggesting their use as single agents or in combination with other therapies. Collectively, these findings establish <i>NT5E</i> as a promising prognostic biomarker and therapeutic target in LUAD, particularly in the context of immune cell infiltration.</p>