Abstract About 80% to 85% of lung cancers are non-small cell lung cancers (NSCLC), including lung adenocarcinoma (LUAD, 40% of lung cancers) and lung squamous cell carcinoma (LUSC, 25% to 30% of lung cancers). Fibrinogen is an extracellular matrix protein composed of three polypeptide chains with fibrinogen alpha (FGA), beta (FGB), and gamma (FGG). A recent genome-scale screening reveals that loss of FGA affects the acceleration of tumor growth and metastasis of lung cancer, but the mechanism remains elusive. Based on our bioinformatics analysis, genetic alterations of FGA are unlikely to be a frequent event in human lung cancers. However, our expression analysis showed a low expression of FGA in human lung cancer tissues, including LUAD and LUSC. DNA hypermethylation in the promoter region of FGA is correlated with low expression of FGA in human LUAD tissues. Furthermore, FGA knockout promotes but the administration of FGA inhibits LUAD cell growth, migration, and invasion, as well as tumor colonization in the lung. Our functional analysis revealed the FGA-mediated regulation of tumor growth and metastasis through apoptosis and EMT is also involved in the integrin-AKT signaling pathway in LUAD cells in vitro and xenograft tumor model in vivo. These data suggest that FGA may play a suppressive role in LUAD cells to inhibit tumor growth and metastasis through induction of apoptosis and inhibition of EMT. In LUAD cells, FGA can bind integrin α5 and reduce phosphorylation of AKT, leading to an inhibition of mTOR signaling. The administration of FGA may provide a new therapeutic approach to inhibit LUAD cell growth and metastasis. However, FGA may also affect TME cells in vivo, such as endothelial cells, leading to the various roles of FGA in tumor growth and metastasis. Citation Format: Xinran Wang, Mary Katherine Swartz, Runhua Liu. Fibrinogen suppresses tumor growth and metastasis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2505.