GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells
Menée sur des souris femelles avec glioblastome, cette étude met en évidence un mécanisme spécifique par lequel l'activation du récepteur de l'acide gamma-aminobutyrique favorise la progression tumorale en augmentant la voie de signalisation impliquant le transporteur cationique d'acides aminés 2, la L-arginine et l'oxyde nitrique synthase, ce qui conduit à l'inhibition des lymphocytes T par les cellules myéloïdes suppressives de type granulocytaire
Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2–L-arginine–nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy.
Nature Cancer , article en libre accès, 2026