Gamma-aminobutyric acid signaling in triple-negative breast cancer: association with resistance to combined immunotherapy and chemotherapy

Neurotransmitter signaling has emerged as a critical but underexplored regulator of tumor progression and therapeutic resistance. Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, has been implicated in multiple malignancies; however, its role in chemoimmunotherapy resistance for triple-negative breast cancer (TNBC) remains largely unknown. Clinicopathological data from 589 TNBC patients (2018–2021) were retrospectively analyzed. GABA levels were detected by immunofluorescence, immunohistochemistry and ELISA. Public transcriptome dataset GSE241876 was analyzed to explore resistance-related pathways. The 4T1 syngeneic mouse model was applied to assess anti-tumor effect of GAD-inhibitor 3-MPA combined with chemoimmunotherapy. Survival and treatment-response analyses were performed. GABA, GAD1, GAD2 and GABA-receptor were significantly upregulated in chemoimmunotherapy-resistant TNBC. Elevated GABA was correlated with higher recurrence risk, shorter survival and worse neoadjuvant treatment response ( p < 0.05). ROC curve analysis identified a GABA-MFI cutoff of 40 (AUC = 0.802, p < 0.001). GABA-high patients had a lower radiological response rate (5/17 vs 23/30, p = 0.006). In mouse models, pharmacological inhibition of GABA biosynthesis restored chemoimmunotherapy sensitivity. Our retrospective clinical and preclinical data suggest GABA signaling is associated with chemoimmunotherapy resistance in TNBC. GABA shows potential as a prognostic biomarker, and GABA-targeted intervention represents a promising preclinical strategy. Prospective external validations are required for clinical translation.