Neutrophil extracellular traps predict poor response and prognosis in non-small cell lung cancer immunotherapy

Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet reliable biomarkers for predicting response remain limited. Neutrophil extracellular traps (NETs) may influence tumor immunity, but their clinical significance in NSCLC is unclear.

To evaluate the predictive and prognostic value of NETs in advanced NSCLC patients treated with chemo-immunotherapy.

A retrospective cohort study.

Pretreatment formalin-fixed paraffin-embedded biopsies from 46 stage IV NSCLC patients receiving first-line chemo-immunotherapy were analyzed by multiplex immunofluorescence to quantify NETs, CD8⁺ T cells, and cancer-associated fibroblasts (CAFs). Survival and correlation analyses were performed.

High NETs' density was associated with shorter progression-free survival (PFS: 8 vs 20 months, p = 0.028) and overall survival (OS: 14.7 vs 29.8 months, p = 0.0046). NETs' levels inversely correlated with CD8⁺ T-cell density (R = -0.33, p = 0.025) and showed a trend toward positive correlation with CAFs (R = 0.27, p = 0.07). Poorer survival was observed when a high density of CAFs and CD8⁺ T cells was present within 30 µm of NETs. Multivariate Cox analysis confirmed high NETs as an independent prognostic factor.

NETs predict poor immunotherapy response and survival in advanced NSCLC and interact with CD8⁺ T cells and CAFs to potentially mediate resistance. NETs represent a promising biomarker and potential therapeutic target for enhancing immunotherapy efficacy in NSCLC.