{
  "abstract": "Recurrence remains a significant clinical challenge for triple-negative breast cancer patients and radiotherapy (RT) is a key therapeutic tool that significantly reduces the risk of relapse. Despite this, patients with chronic lymphopenia and a high neutrophil:lymphocyte ratio (NLR) experience recurrence at significantly higher rates than those whose hematological biomarkers return to baseline post-RT, and there are currently no treatments to prevent this relapse. Here, we utilized in vivo mouse models of lymphocyte-deficiency to identify the mechanism behind systemic immune status and recurrence. Using a model of RT-induced circulating tumor cell (CTC) colonization, we found that neutrophils are sustained in the irradiated, lymphocyte-deficient mammary tissue up to 10 days post-RT. Persistent neutrophil accumulation was accompanied by excessive vascular remodeling and tumor cell colonization of the mammary tissue, both of which were abated upon systemic neutrophil depletion. Neutrophils in the colonization-permissive microenvironment exhibited a state of pathological activation consistent with a polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype that was not seen in systemic compartments, highlighting a microenvironment-induced phenotype shift. This phenotype was recapitulated in vitro when naive neutrophils were exposed to the secretome of RT-induced senescent endothelial cells (ECs). We found that these activated neutrophils then regulated the dysfunction of irradiated ECs in a canonical NF-kB-dependent manner, increasing their barrier permeability and activating downstream inflammatory signals. Our findings not only establish neutrophils as a critical component of tumor cell colonization in lymphocyte-deficient subjects but also uncover a positive feedback loop between neutrophils and irradiated vasculature that leads to aberrant tissue remodeling and ultimately tumor cell colonization. This work deepens our understanding of how systemic factors influence treatment-damaged microenvironments, which could ultimately lead to identification of molecular targets for prevention of RT failure.",
  "abstract_shown": true,
  "affiliations": [
    "Vanderbilt University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "S. E. Martello"
    },
    {
      "name": "B. H. Stevenson"
    },
    {
      "name": "H. Korbey"
    },
    {
      "name": "K. C. Corn"
    },
    {
      "name": "T. Zhu"
    },
    {
      "name": "E. J. Lin"
    },
    {
      "name": "M. Paul"
    },
    {
      "name": "K. E. Stubenrauch"
    },
    {
      "name": "J. Wang"
    },
    {
      "name": "A. Perez"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Rafat"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4cp3a0d5n1tar.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.03.756445",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1.full",
  "id": "4cp3a0d5n1tar",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7220683027",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4cp3a0d5n1tar.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:12Z",
      "native_id": "10.64898/2026.10.03.756445",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue",
  "title_text": "Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:12Z",
  "url": "https://research.draconitic.com/paper/4cp3a0d5n1tar",
  "venue": "bioRxiv",
  "versions": []
}