Neutrophil Extracellular Traps in the Tumor Microenvironment: Mechanisms, Immune Regulation, and Implications for Immune Checkpoint Inhibitor Therapy

Abstract

Neutrophil extracellular trap formation (NETosis) has emerged as a pivotal regulator of the tumor immune microenvironment and a key determinant of response to cancer immunotherapy. NETs—web-like chromatin fibers decorated with histones, citrullinated histone H3, myeloperoxidase, neutrophil elastase, and matrix metalloproteinase-9—are induced by tumor-derived signals through classical lytic, vital non-lytic, and gasdermin D-dependent pathways, and exert context-dependent, predominantly pro-tumorigenic effects. Within the tumor microenvironment, NETs remodel the stroma, suppress CD8+ T-cell, natural killer-cell, and dendritic-cell function, promote regulatory T-cell and M2 macrophage polarization, and physically shield tumor cells from cytotoxic attack. By carrying programmed death-ligand 1 and driving T-cell exhaustion and immune exclusion, NETs compromise the efficacy of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1, CTLA-4, and next-generation checkpoints, as well as adoptive cell therapies. This review synthesizes the molecular mechanisms of NETosis, its multifaceted immunomodulatory roles, and emerging NET-derived biomarkers—including MPO-DNA and citrullinated histone H3-DNA complexes—that may predict immunotherapy response and toxicity. We further appraise therapeutic strategies, including PAD4 inhibitors, DNase I, CXCR2 antagonists, and nanoparticle-based platforms, and underscore the need for standardized NET quantification, careful preservation of host defense, and biomarker-guided clinical trials to translate NET modulation into durable improvements in immunotherapy outcomes.