ITGA8 suppresses proliferation and metastasis of lung adenocarcinoma through the inhibition of glycolysis.

Lung adenocarcinoma (LUAD) is the most prominent subtype of non-small cell lung cancer characterized by high morbidity and mortality. While integrins are known regulators of tumor progression, most function as oncogenes; however, the role of ITGA8 in LUAD remains distinct and poorly understood. Here, we integrated bioinformatics analyses across multiple cohorts (TCGA, GEO) with experimental validation using clinical samples, in vitro assays, and in vivo xenograft models to investigate the function and mechanism of ITGA8. Unlike upregulated integrin members (e.g., ITGA2, ITGA11), ITGA8 was significantly downregulated in LUAD tissues, and its low expression correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Functionally, ITGA8 overexpression potently inhibited LUAD cell proliferation, migration, invasion, and xenograft tumor growth. Mechanistically, ITGA8 acted as a metabolic gatekeeper by suppressing aerobic glycolysis (decreasing ECAR, glucose uptake, and lactate production) via the activation of the AMPK signaling pathway and subsequent inhibition of the mTOR/S6K/4EBP1 axis. Notably, treatment with an AMPK inhibitor reversed the ITGA8-mediated suppression of glycolysis and malignant phenotypes. Furthermore, analysis of the tumor microenvironment revealed that ITGA8 expression was positively correlated with stromal score and regulatory T cells (Tregs) but robustly negatively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs). Collectively, our findings establish ITGA8 as a novel tumor suppressor in LUAD that constrains malignancy by reprogramming glycolytic metabolism and remodeling the immune microenvironment, suggesting its potential as a prognostic biomarker and therapeutic target.