Tumor-derived GABA promotes lung cancer progression by influencing TAMs polarization and neovascularization

Background: Gamma-aminobutyric acid (GABA), a common neurotransmitter, has been found in various cancers but its origin and its role in the tumor immune microenvironment remains unclear. Methods: Here, we reported the expression of glutamate decarboxylase 1 (GAD1, converting glutamate into GABA) in lung cancer tissues based on the publicly available database, and explored the effects and underlying mechanism of GABA on lung cancer progression. Results: Compared with normal tissues, GAD1 was aberrantly overexpressed in lung adenocarcinoma (LUAD) based on TCGA database. Furthermore, the LUAD patients' overall survival was negatively correlated with the GAD1 expression levels. Our work found that a GABAa receptor inhibitor had a therapeutic effect on mouse tumors and significantly reduced tumor size and weight. Further experiments showed that GABA derived from tumor cells promoted tumor progression not by directly affecting cancer cells but by affecting macrophages polarization in the tumor microenvironment. We found that GABA inhibited the NF-kappa B pathway and STAT3 pathway to prevent macrophages from polarizing towards M1 type, while promoting macrophage M2 polarization by activating the STAT6 pathway. GABA was also found to promote tumor neovascularization by increasing the expression of FGF2 in macrophages. Conclusions: These results suggest that GABA affects tumor progression by regulating macrophage polarization, and targeting GABA and its signaling pathway may represent a potential therapy for lung cancer.