Lactate-activated astrocytes promote NSCLC brain metastasis through extracellular vesicle-mediated miR-8085/TRIM67/ELK1 signaling axis

Brain metastasis represents an advanced complication in non-small cell lung cancer (NSCLC), characterized by therapeutic resistance and dismal survival outcomes. Although astrocytes are known to influence tumor progression within the brain microenvironment, their prognostic significance and mechanistic contributions to NSCLC brain metastasis (NSCLC-BM) remain largely unresolved. In this study, we analyze brain metastatic tumors from 66 patients with NSCLC and demonstrate that high infiltration of astrocytes is significantly associated with reduced overall survival. Functional assays reveal that astrocytes enhance the stemness of metastatic tumor cells, a phenotype that is significantly attenuated by silencing astrocytic monocarboxylate transporter 1 (MCT1), thereby blocking lactate uptake. Mechanistically, lactate reprograms astrocytes to release extracellular vesicles enriched in miR-8085, which downregulates the E3 ubiquitin ligase TRIM67 in tumor cells. This suppression stabilizes the transcription factor ELK1 through inhibition of ubiquitin-mediated degradation, promoting stemness maintenance and tumorigenic capacity. Clinically, low TRIM67 and high ELK1 expression correlate with poorer survival in patients with NSCLC-BM. Together, our findings uncover a novel lactate-induced miR-8085/TRIM67/ELK1 signaling cascade that drives brain metastasis progression and highlight potential prognostic biomarkers and therapeutic targets for patients with NSCLC involving the brain.