# The Neutrophil–NET Axis in Immune Checkpoint Inhibitor Resistance in Non-Small Cell Lung Cancer: Roles, Biomarkers and Therapeutic Opportunities

## TL;DR

This paper reviews how neutrophils and their extracellular traps (NETs) contribute to resistance against immunotherapy in non-small cell lung cancer and explores potential strategies to overcome this resistance.

## Contribution

The paper systematically reviews the role of neutrophils and NETs in ICI resistance and proposes therapeutic strategies targeting these elements in NSCLC.

## Key findings

- Neutrophils and NETs promote an immunosuppressive tumor microenvironment in NSCLC.
- NETs contribute to immune checkpoint inhibitor resistance by fostering an immune-excluded tumor environment.
- Targeting neutrophils and NETs offers potential therapeutic opportunities to improve immunotherapy outcomes in NSCLC.

## Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death. Although molecular stratification and multimodal therapy have improved outcomes in selected patients, overall prognosis is still limited by late diagnosis, heterogeneity, and treatment resistance. Immune checkpoint inhibitors (ICIs) have substantially improved survival outcomes in a subset of patients; however, the overall benefit remains limited, and both primary and acquired resistance are common. Neutrophils, as key effectors of innate immune responses, can be activated by diverse stimuli and release neutrophil extracellular traps (NETs). Growing evidence indicates that neutrophils and NETs contribute to remodeling of the tumor microenvironment (TME) in NSCLC, promoting resistance to ICIs. This review systematically summarizes the biological features, key molecular pathways, and inducing factors of neutrophils and NETs in lung cancer and synthesizes evidence supporting their roles as biomarkers of ICI efficacy and prognosis. We further focus on the mechanisms by which NETs mediate immunosuppression and foster an immune-excluded TME, thereby driving resistance to immunotherapy. In addition, we outline potential therapeutic and combination strategies targeting neutrophils and NETs, providing a theoretical basis for developing optimized immunotherapy approaches for NSCLC that target neutrophils and NETs.