{
  "abstract": "Background: The efficacy of immune checkpoint inhibitors (ICI) in diffuse large B-cell lymphoma (DLBCL) is often limited by the immunosuppressive tumor microenvironment (TME), which comprises diverse cellular and non-cellular components. Among these, neutrophil extracellular traps (NETs) have emerged as potential immunomodulators that may contribute to immune suppression; however, their functional significance and regulatory mechanisms in DLBCL remain elusive.\n\nMethods: NETs levels were evaluated in DLBCL patient specimens and their effects on clinical outcomes were analyzed. Using a syngeneic murine lymphoma model, we assessed the therapeutic effect of DNase I-mediated NET degradation, both alone and in combination with anti-PD-L1 antibody. Mechanistic investigations included in vivo macrophage depletion, transcriptomic profiling, and in vitro assays under normoxic and hypoxic conditions.\n\nResults: NETs were significantly elevated in DLBCL tissues and were correlated with advanced disease stage, elevated PD-L1 expression, and poor survival. Deoxyribonuclease I (DNase I) treatment potently inhibited tumor growth and exhibited marked synergy with PD-L1 blockade. This combination therapy robustly reduced immunosuppressive macrophages and myeloid-derived suppressor cells while enhancing CD8+ T cell infiltration and function. Mechanistically, NETs promoted T cell exhaustion primarily through macrophage-dependent pathways and affected by the oxygen tension: under normoxia, NETs drove macrophages into a dysfunctional phenotype, whereas under hypoxia, they were associated with PI3K-Akt pathway to drive macrophages toward an immunosuppressive phenotype. Furthermore, hypoxia promoted NET formation via the HIF-1α/IL-8 axis, establishing a self-reinforcing immunosuppressive circuit.\n\nConclusion: Our study identifies NETs as pivotal regulators of immunosuppression in DLBCL and demonstrates that targeting NETs with DNase I effectively remodels the TME and enhances ICI efficacy, providing a compelling rationale for clinical translation of this combinatorial approach.\n\nGraphical Abstract:\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08789-5.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Hematology, Northern Jiangsu Institute of Clinical Medicine, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Huai’an City, Jiangsu Province 223300 China",
    "Key Laboratory of Autoimmune Disease of Huai’an Government; No. 1, West Huanghe Road, Huaiyin District, Huai’an City, Jiangsu Province 223300 China",
    "Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing City, Jiangsu Province 211166 China",
    "Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing City, Jiangsu Province 211166 China",
    "Department of Hematology; the Huai’an Clinical College of Xuzhou Medical University; No. 1, West Huanghe Road, Huaiyin District, Huai’an City, Jiangsu Province 223300 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Kebing Lv"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhengmei He"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Qiuni Chen"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuye Shi"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Lulu Wei"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yang Su"
    },
    {
      "affs": [
        0
      ],
      "name": "Dongnan Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Shujun Tang"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Kening Li"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Chunling Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Liang Yu",
      "orcid": "0000-0002-0803-5801"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bf97y48pagksp.bib",
  "cited_by": 0,
  "doi": "10.1186/s12967-026-08789-5",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13741572/",
  "id": "bf97y48pagksp",
  "issns": [
    "1479-5876"
  ],
  "landing_url": "https://doi.org/10.1186/s12967-026-08789-5",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2403|Neutrophil, Myeloperoxidase and Oxidative Mechanisms"
    ]
  ],
  "openalex": "W7203731802",
  "pdf_url": null,
  "pmcid": "PMC13741572",
  "pmid": "42995596",
  "published": "2026-08-19",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/bf97y48pagksp.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T12:22:37Z",
      "native_id": "PMC13741572",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12967-026-08789-5"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Neutrophil, Myeloperoxidase and Oxidative Mechanisms",
      "subfield": "immunology"
    }
  ],
  "title": "Hypoxia-induced NETs establish a self-reinforcing immunosuppressive circuit that can be targeted to enhance immunotherapy in DLBCL",
  "title_text": "Hypoxia-induced NETs establish a self-reinforcing immunosuppressive circuit that can be targeted to enhance immunotherapy in DLBCL",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:22:37Z",
  "url": "https://research.draconitic.com/paper/bf97y48pagksp",
  "venue": "Journal of Translational Medicine",
  "versions": []
}