GABA Immune Pathway Drives Sex-Specific Glioblastoma Growth in Females, Study Finds
核心洞察
A new study published in Nature Cancer reveals that the neurotransmitter GABA selectively fuels glioblastoma (搜索) growth in females by reprogramming granulocytic MDSCs through the L-Arg–NOS2 pathway.
Blocking GABA receptor B (GABBR (搜索)) signaling with the antagonist CGP 35348 significantly extended survival in female mouse models of glioblastoma (搜索) but had no effect in males.
Human tumor biopsies confirmed that female glioblastoma (搜索) patients have higher GABA levels and GABBR (搜索) expression in tumor-infiltrating immune cells compared to male patients.
Researchers at Sylvester Comprehensive Cancer Center (搜索), part of the University of Miami’s Miller School of Medicine, have identified a critical sex-specific biological mechanism that explains how glioblastoma (搜索) — the most common and lethal form of brain cancer — exploits different immune pathways depending on biological sex. The study, published in Nature Cancer, demonstrates that the neurotransmitter GABA (gamma-aminobutyric acid) selectively fuels tumor growth in females by reprogramming granulocytic myeloid-derived suppressor cells (gMDSCs), a class of immune cells that suppress anti-tumor T-cell activity.
“We have a growing appreciation that cancer doesn’t act the same way in men and women. There are differences in incidence rates; there are differences in treatment responses; there are differences in outcomes,” said Defne Bayik, Ph.D., assistant professor of molecular and cellular pharmacology and senior author of the study. “But we don’t really have a good fundamental understanding of the mechanisms underlying these observational studies.”
Sex-Specific MDSC Subsets Drive Divergent Disease Biology
In previous work, Bayik and colleagues established that glioblastoma (搜索) exhibits sex-specific differences in its immune landscape: monocytic MDSCs (mMDSCs) are associated with disease in male models, while granulocytic MDSCs correlate with worse clinical outcomes exclusively in females. The new study sought to uncover the mechanistic basis for this divergence.
By reanalyzing drug candidates predicted to target individual MDSC subsets using a network medicine approach, the team identified three GABA pathway modulators among the top 20 clinically approved drugs predicted to target gMDSCs. Given that GABA is the most abundant inhibitory neurotransmitter in the brain, the researchers investigated whether MDSCs respond to GABA signaling.
They found that expression of both GABBR (搜索) heterodimer subunits — Gabbr1 and Gabbr2 — was higher in mouse bone-marrow-derived gMDSCs compared to mMDSCs. Critically, overnight treatment with GABA led to intracellular accumulation of L-Arginine (L-Arg) and upregulation of arginine biosynthesis and metabolism pathways specifically in gMDSCs from female mice, with no notable metabolic alterations in mMDSCs from female mice or in any MDSC subsets from male mice.
GABA Reprograms Arginine Metabolism Through the L-Arg–NOS2 Axis
Further analysis revealed that GABA stimulation upregulated expression of the Slc7a2 gene, which encodes the L-Arg transporter CAT2B, specifically in gMDSCs from female mice. This led to a significant increase in NOS2 (nitric oxide synthase 2) protein levels in gMDSCs from female mice treated with GABA or the GABBR (搜索)-selective agonist baclofen, but not with a GABAAR-selective agonist. ARG1 levels remained unchanged across all conditions.
“Baclofen-treated gMDSCs from female mice further reduced T cell proliferation compared to vehicle-treated controls,” the authors reported. In contrast, gMDSCs from CAT2-knockout female mice did not alter their function in response to baclofen, confirming that functional gMDSC reprogramming by GABBR (搜索) signaling relies on the L-Arg metabolic pathway. Inhibition of NOS2 by aminoguanidine reversed baclofen-induced T cell suppression, and pharmacological scavenging of peroxynitrite with uric acid or MCI-186 (edaravone) fully mitigated the effect.
GABBR (搜索) Antagonism Extends Survival Exclusively in Female Models
In preclinical experiments, female immunocompetent mice orthotopically implanted with syngeneic GBM models (SB28 or GL261) and treated with baclofen succumbed to GBM earlier compared to vehicle-treated mice. This intervention did not impact disease outcomes in immunocompetent male mice or immunocompromised mice of either sex, and neither GABA nor baclofen affected the proliferation of GBM cell lines in vitro — confirming that the protumorigenic effect relies on the tumor-immune microenvironment.
Conversely, systemic treatment with the GABBR (搜索) antagonist CGP 35348 significantly improved survival in immunocompetent female mice bearing SB28 or GL261 tumors, while it did not affect survival of male mice. Administration of CGP 35348 led to a significant reduction in NOS2 expression from tumor-infiltrating gMDSCs in females, an effect not observed in tumor-infiltrating mMDSCs or macrophages. Depletion of gMDSCs with an anti-Ly6G antibody did not improve survival beyond CGP 35348 treatment, supporting the conclusion that GABBR inhibition improves survival by reducing NOS2 production from tumor-infiltrating gMDSCs.
Human Tissue Validation Confirms Clinical Relevance
The translational relevance of these findings was validated in human samples. Analysis of a publicly available single-cell RNA-sequencing dataset (GSE117891) revealed that tumor-infiltrating immune cells from female glioblastoma (搜索) patients had enriched GABA transcriptional signatures and higher GABA receptor expression profiles compared to males. Notably, tumor-associated macrophages, microglia, and neutrophils/gMDSCs from women had significantly higher GABBR1 and GABBR2 expression compared to men, while no sex difference was observed in monocytes/mMDSCs.
Mass spectrometry analysis showed that high-grade brain tumors from women had higher GABA concentrations compared to tumors from men. Similarly, SB28 tumors from female mice had significantly higher GABA levels than those from male mice. Consistent with the mouse data, baclofen stimulation induced NOS2 — but not ARG1 — upregulation in gMDSCs from healthy female donor peripheral blood mononuclear cells.
Broader Implications for Sex-Specific Cancer Immunotherapy
“Glioblastoma (搜索) may be more common in men, but women still constitute 40% of patients,” said Bayik. “By identifying these differences, we can better tailor treatments for both men and women.”
The study underscores the importance of considering sex as a biological variable in both preclinical and clinical research. Because suppressive MDSCs are heavily recruited by many other aggressive cancer types, these sex-specific metabolic findings may have therapeutic applications far beyond glioblastoma (搜索). The authors note that future research should explore neurotransmitter receptor modulators for regulation of tumor-immune interactions, alone or in combination with established immunotherapies.
The research was led by Defne Bayik, Ph.D., and Asmita Pathak, Ph.D., a former postdoctoral fellow of the Bayik Lab, and published in Nature Cancer (DOI: 10.1038/s43018-026-01192-5).