Abstract Introduction: Lung adenocarcinoma (LUAD) is the deadliest cancer worldwide. Many efforts are made to search for new biomarkers to screen for immunotherapy candidates and predict the response. Neural Precursor Cell Expressed, developmentally down-Regulated 9 (NEDD9), is predominantly expressed in many cancer types but has not been studied yet in lung adenocarcinoma. Herein, we analyzed the association of NEDD9 with immune inhibitory components to understand its immune landscape in lung adenocarcinoma. Methods: Gene expression profiles were retrieved from The Cancer Genomic Atlas Lung Adenocarcinoma cohort (n = 567). We used TIMER 2.0 for immune inhibitory cell infiltrates analysis. Tumor mutational burden (TMB) was measured using the cBioPortal tool. The enrichment analysis of function and signaling pathways of DEGs in LUAD was done by gene ontology (GO) using Enrichr. Results: NEDD9 is differentially expressed in LUAD tissues (P < 0.00). High NEDD9 expression had better overall survival prognostic value in LUAD patients (HR: 0.66, 95% CI: 0.49 - 0.89, P = 0.0221) compared to low expression. NEDD9 expression was positively correlated with the infiltration of cancer-associated fibroblasts and macrophage M2 cells (spearman’s ρ = 0.257, P < 0.001, ρ = 0.266, P < 0.001, respectively), but negatively with myeloid-derived suppressor cells (MDSC) (ρ = -0.344, P < 0.001). Moreover, survival analysis based on NEDD9 expression and MDSC levels revealed a better OS group identified by low MDSC levels and low NEDD9 expression after adjustment for age, stage, and purity. In terms of immune checkpoint genes’ expression, NEDD9 expression was directly correlated with CTLA-4, PD-1, PD-L1, VSIR, and LAG-3 (ρ > 0.2, Q value < 0.05). TMB was inversely associated with NEDD9 expression (ρ = -0.1, P < 0.001). GO analysis showed that genes co-expressed with NEDD9 were mainly in the phagocytic vesicles and participated in biological processes of cellular response to interferon-gamma by molecular function such as cysteine-type endopeptidase activity involved in apoptotic signaling pathways. Conclusion: We found that NEDD9 expression is a useful biomarker of immunosuppression in LUAD patients and can predict the response to immunotherapy. Our results suggest that NEDD9 is a favorable prognostic biomarker, which could be explained by low MDSC. Further studies are needed for a better understanding of the NEDD9 value in LAUD. Citation Format: Leen M. Al-Kraimeen, Yaqeen M. Al-Kraimeen. NEDD9 as a prognostic biomarker and its immune landscape in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2214.