KDM1A-associated tumor–myeloid communication and extracellular vesicle-mediated microglia-like responses in lung cancer brain metastasis

Introduction Lung cancer brain metastasis is shaped by reciprocal interactions between tumor cells and the brain microenvironment, yet whether KDM1A/LSD1 influences this communication through tumor-derived extracellular vesicles (EVs) remains unclear. Methods Here, we combined within-patient single-cell transcriptomic analysis with genetic and pharmacological LSD1 perturbation, EV-based functional assays, and an intracranial xenograft model to define an LSD1-associated tumor-myeloid communication phenotype. Results Single-cell analysis identified a reproducible KDM1A co-expression-associated tumor-cell state characterized by coordinated communication- and microenvironment-remodeling programs and recurrent APP-CD74- and MDK-related signaling patterns. Among the prioritized candidates, MDK showed the most consistent experimental response to LSD1 knockout, with concordant reductions in donor-cell mRNA, cellular protein and EV-associated protein. Functionally, EVs derived from LSD1-deficient tumor cells shifted HMC3 microglia-like cells toward a mixed inflammatory and immunoregulatory state and altered their secretory output. Conditioned medium from these EV-exposed HMC3 cells subsequently suppressed H1299 proliferation and enhanced apoptosis, indicating a secondary tumor-myeloid-tumor paracrine effect. Pharmacological LSD1 inhibition produced a partially overlapping functional phenotype. In mice with established intracranial tumors, LSD1-KO-EV treatment was associated with lower endpoint ex vivo brain bioluminescence, with representative H&E sections showing a qualitatively concordant pattern. Discussion These findings support EV-mediated tumor-myeloid communication as one consequence of LSD1 perturbation and nominate MDK-associated EV remodeling for direct mechanistic testing.