Neutrophil Extracellular Trap Reprograms Cancer Metabolism to Form a Metastatic Niche Promoting Non-Small Cell Lung Cancer Brain Metastasis

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.

Keywords: brain metastasis; metabolic reprogramming; metastasis‐initiating cells; neutrophil extracellular traps; non‐small cell lung cancer.