MEIS3 Drives Malignant Progression and Contributes to an Immunosuppressive Microenvironment in Stomach Adenocarcinoma

Stomach adenocarcinoma (STAD) represents the most prevalent malignant tumor in the digestive system with unfavorable clinical outcomes worldwide. MEIS3, a member of the TALE homeobox family, has been linked to diverse cellular functions; however, its specific contribution to STAD remains elusive. In this study, we systematically deciphered the oncogenic potential of MEIS3 through integrated bioinformatic analysis and rigorous in vitro validation. Public databases were utilized to investigate MEIS3 expression and its correlation with clinicopathological features. Gain- and loss-of-function assays were performed to identify the role of MEIS3 in STAD cells proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). The underlying signaling axis was verified by western blotting. Furthermore, the relationship between MEIS3 and tumor immune microenvironment was evaluated using multiple algorithms. Our results demonstrated that MEIS3 was significantly upregulated in STAD tissues and cell lines compared with normal controls. High MEIS3 expression was closely associated with advanced TNM stage and poor overall survival, disease-specific survival, and progression-free interval. Functionally, overexpression of MEIS3 markedly promoted the proliferation, migration, invasion, and EMT capacity of STAD cells, whereas MEIS3 knockdown exerted opposite effects. Mechanistically, MEIS3 exerted its oncogenic activity via activating the PI3K/AKT signaling pathway. Additionally, MEIS3 expression was significantly correlated with immune cell infiltration, microsatellite instability, tumor mutational burden, immune checkpoint gene expression, and immunotherapy response. Collectively, these data establish MEIS3 as a pivotal regulator of both cancer cell intrinsic properties and the extrinsic immune landscape in STAD, suggesting its utility as a novel prognostic marker and therapeutic candidate.