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

[BACKGROUND] 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.

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

[DESIGN] A retrospective cohort study.

[METHODS] 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.

[RESULTS] High NETs' density was associated with shorter progression-free survival (PFS: 8 vs 20 months,  = 0.028) and overall survival (OS: 14.7 vs 29.8 months,  = 0.0046). NETs' levels inversely correlated with CD8 T-cell density ( = -0.33,  = 0.025) and showed a trend toward positive correlation with CAFs ( = 0.27,  = 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.

[CONCLUSION] 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.