Bo Chen, Karrie Mei Yee Kiang, Fangkun Liu, Chuntao Li, Xizhe Li, Chen Weiwei, Xin Fu, Gelei Xiao, Jingyi Sun, Erhan Da, Junbo Liao, Hongshu Zhou, Li Meng, Li Zhou, Tao Song, Longbo Zhang, Gkk Leung, Liyang Zhang
Abstract Non‐small cell lung cancer (NSCLC) is the leading cause of brain metastases (BMs) and is characterized by a poor prognosis and limited response to standard treatments. Multi‐omics sequencings, integrating spatial transcriptomics, metabolomics, single‐cell RNA sequencing, bulk proteomics, and metabolomics, are conducted to analyze tumor and blood specimens from 34 patients with NSCLC with or without BMs from the Xiangya Hospital NSCLC (XY‐NSCLC) and Queen Mary Hospital NSCLC (QMH‐NSCLC) cohorts. This investigation identified LOX + Malig‐5 cells as metastasis‐initiating cells (MICs) that are significantly associated with poor prognosis. MICs colocalize with specific neutrophil subtypes, which facilitate the formation of neutrophil extracellular traps (NETs) within the metastatic niche. Mechanistically, a NET‐KRT10 signaling axis that mediates the interaction between NET‐releasing neutrophils and LOX + Malig‐5 cells is discovered, thereby promoting epithelial–mesenchymal transition (EMT) and metastasis. Furthermore, metabolic profiling reveals elevated palmitic acid levels in the resulting metastatic niche, which emerges as a crucial metabolic driver in BMs. Using an AI‐driven prediction model and in vitro/in vivo assays, fatty acid synthase inhibitor TVB‐2640 is identified as a potential therapeutic agent for disrupting metabolic vulnerability and suppressing NSCLC BMs. These findings provide novel insights into NET‐dependent cellular interactions that sustain the pro‐metastatic microenvironment underlying NSCLC BMs, offering robust development of novel metabolism‐based therapeutic strategies to combat this lethal complication.