GABRP Mediates GABA-A Receptor to Shape Tumor Immunosuppressive Microenvironment and Promote Tumor Immune Escape and Corresponding Targeted Therapy

Abstract

Background: Tumor immune evasion mediated by the immunosuppressive tumor microenvironment (TME) remains a major obstacle in cancer therapy. The γ-aminobutyric acid receptor π subunit (GABRP) is aberrantly expressed in cancers, but its role in immune evasion is poorly defined. Objective: To elucidate the mechanism of GABRP-driven TME remodeling and evaluate its therapeutic potential. Materials and Methods: Pan-cancer bioinformatics analysis (TCGA, GEPIA2, cBioPortal) assessed GABRP expression, survival associations, and immune infiltration across 33 cancers. Functional studies included GABRP knockdown in glioma cells (U87/U251) via lentiviral RNAi, proliferation/migration assays (CCK-8, scratch test), and pathway analysis. Subcutaneous xenografts in BALB/c-nu mice evaluated the GABA_A inhibitor Amentoflavone. Immune profiling utilized ssGSEA and TIMER. Results: GABRP was overexpressed in gliomas and other cancers (breast, gastric), correlating with poor prognosis (HR = 1.8, p = 0.008) and enriched immunosuppressive cells (Tregs, M2 macrophages). Knockdown suppressed proliferation (IC50↓42%), migration (> 50% delay, p < 0.01), and PI3K/AKT signaling. Amentoflavone reduced tumor volume by 68% (p < 0.001) and reversed GABA-mediated T cell inhibition. Discussion: GABRP promotes immune evasion via GABA overproduction, recruiting Tregs/M2 macrophages to establish an immunosuppressive TME. Targeting GABRP or GABA signaling (e.g., Amentoflavone) restores antitumor immunity. Limitations include cohort size and tissue-specific heterogeneity. Conclusion: GABRP is a key regulator of tumor immunosuppression. Dual strategies—blocking GABRP expression or GABA signaling—offer novel therapeutic avenues. Clinical validation is needed to advance precision oncology.