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

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.

Keywords

immune checkpoint inhibitors, neutrophils, resistance, mechanism / combination therapy

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