Abstract

Emerging evidence has demonstrated that lung cancer patients with brain oligometastases (oligo-BMs) could benefit from local radical therapies. Despite rapid advancements in the treatment of oligometastatic disease, the molecular determinants governing the oligometastatic phenotype in the central nervous system remain elusive. We performed 1021-panel sequencing, transcriptome profiling, DNA methylation mapping, and multiplex immunohistochemistry on 20 paired primary lung adenocarcinoma and oligo-BMs specimens to delineate their evolutionary dynamics and microenvironmental characteristics. A pronounced intertumor heterogeneity was observed between primary tumors (PTs) and oligo-BMs, while intratumoral heterogeneity was conserved across lesions. Subclonal analysis and phylogenetic reconstruction demonstrated that oligo-BMs exhibited predominant polyclonal seeding patterns and parallel progression trajectories. Moreover, oligo-BMs displayed a more immunosuppressed microenvironment compared to PTs, characterized by attenuated immunogenic cell death signatures, downregulation of immune-activated pathways, and diminished infiltration of activated immune cells (including B cells, NK cells, and Th1 cells). The methylation levels at functional genomic regions were highly concordant between PTs and oligo-BMs. Notably, we identified NLGN1 as a potential regulator of oligo-BM, where the hypermethylation at its genebody regions was mechanistically associated with transcriptional upregulation. Clinical validation revealed that NLGN1 was specifically overexpressed in BMs compared to PTs and extracranial metastases, correlating with advanced pathological stages and poor prognosis. In vivo studies further confirmed NLGN1 promotes BM in mice.