GABA shunt metabolism drives smoking-related peri-neuronal brain metastasis by hijacking synaptic signaling

BACKGROUND: Brain metastases are a major clinical challenge with poor prognosis, particularly in patients with a history of smoking. While neurons are abundant in the brain and capable of synaptic interaction with tumor cells, their role in brain metastasis remains poorly understood. Emerging evidence suggests that neuronal activity may contribute to metastatic progression, yet the mechanisms by which smoking alters the brain microenvironment to promote tumor growth are unclear. METHODS: We examined the impact of nicotine exposure on microglia-neuron-tumor interactions in brain metastasis models using in vivo and ex vivo approaches. We analyzed patient-derived brain metastatic tissues, performed molecular and metabolic profiling, and utilized pharmacologic inhibition strategies to dissect the underlying mechanisms of tumor-neuron communication. RESULTS: Our findings reveal a significant association between smoking history and perineural invasion in brain metastases. Nicotine exposure stimulates microglia to release exosomal miR-32-3p, which activates GABAergic neurons and enhances GABA release. GABA acts as a metabolic substrate in the tumor microenvironment, fueling tumor growth through the GABA shunt pathway. Pharmacological inhibition of GABA uptake with FDA-approved GABA transporter (GAT) inhibitors Tiagabine and NO-711 significantly suppress brain metastatic progression in vivo. CONCLUSIONS: This study identifies a novel GABAergic neuron-microglia-tumor signaling axis by which smoking promotes brain metastasis via GABAergic metabolic reprogramming. Targeting GABA uptake on tumor cells using repurposed anticonvulsant drugs offers a promising therapeutic strategy, particularly for patients with smoking-associated brain metastases.