# Targeting neutrophil‐driven immunosuppression: A strategy to overcome immune checkpoint inhibitor resistance

## TL;DR

This paper explores how targeting neutrophils can help overcome resistance to cancer immunotherapy, potentially improving treatment outcomes.

## Contribution

The paper systematically reviews how neutrophils contribute to resistance against immune checkpoint inhibitors and proposes strategies to target them.

## Key findings

- Tumor-associated neutrophils (TANs) contribute to resistance by altering immune responses and promoting tumor growth.
- Neutrophil biomarkers like NLR and TAN abundance predict immunotherapy response and patient prognosis.
- Combining therapies that target TANs with immune checkpoint inhibitors shows promise in clinical trials.

## Abstract

Immune checkpoint blockade (ICB) has revolutionized tumour therapy by relieving immunosuppression and restoring effector T cell cytotoxicity. However, its clinical utility is constrained by low response rates and acquired resistance. Tumour‐associated neutrophils (TANs), key players in tumour immunoregulation, have emerged as critical mediators of ICB responsiveness and resistance, highlighting the therapeutic potential of combining TAN‐targeted strategies with immune checkpoint inhibitors (ICIs). This review systematically synthesizes current knowledge of neutrophils in ICB resistance from several dimensions: (1) clinical indicators of neutrophils, such as the neutrophil‐to‐lymphocyte ratio (NLR) and tissue TANs abundance, as predictors of ICI response and patients prognosis; (2) multifaceted TAN‐involved resistance mechanisms, including direct T cell inhibition, antigen presentation impairment, function modulation of other immune cells, promotion of tumour angiogenesis, and elevation of tumour mutation burden (TMB); (3) combination therapeutic strategies targeting TAN generation/ exhaustion, recruitment, phenotypic polarization, activation, proangiogenic functions, and neutrophil extracellular traps (NETs), along with progress in related clinical trials. Combinatorial approaches integrating TAN‐targeted therapies with ICIs hold substantial promise for overcoming resistance by reshaping the immune microenvironment. Elucidating neutrophil‐mediated resistance mechanisms and optimizing combination strategies will pave the way for precision tumour immunotherapy.

TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burdenNeutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis.Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance.Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.

TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burden

Neutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis.

Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance.

Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.

TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burdenNeutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis.Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance.Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.

TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burden

Neutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis.

Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance.

Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.