{
  "abstract": "Introduction: CAR-T cell therapy has emerged as a highly promising strategy for the treatment of hematological malignancies. However, its efficacy against solid tumors remains limited, mainly due to the establishment of an immunosuppressive tumor microenvironment that impairs CAR-T cell trafficking and functional activation. Given their intrinsic ability to infiltrate solid tumors and interact with several components of the tumor microenvironment, macrophages have emerged as promising candidates for CAR-based cell therapy. However, sources for obtaining macrophages are limited due to their low proliferative capacity, and genetically reprogramming mature monocytes/ macrophages is extremely challenging. Objective: We aimed to generate functional macrophages from human umbilical cord blood-derived CD34+ hematopoietic stem cells (HSCs) engineered to express CARs. Methods: Fresh isolated HSC were in vitro expanded and transduced with a second-generation chimeric lentiviral vector for anti-HER2. Subsequently, expanded CAR-HSC were differentiated into macrophages (MacCD34) in the presence of GM-CSF, M-CSF, and IL-3 for 10 days. Results: Approximately 50% of the CAR-MacCD34 population expressed anti-HER2 CARs and displayed nearly 95% of viability throughout differentiation. Mass spectrometry (MS) and multiparametric flow cytometry analysis revealed upregulation of proteins associated with phagocytosis, matrix remodeling, and degradation, indicating enhanced tumor infiltration potential. In vitro, CAR-MacCD34 showed a significantly improved ability to eliminate and phagocytose HER2+ tumor cells when compared to untransduced MacCD34 cells. Additionally, using high definition microscopy we noted that CAR-MacCD34 cells that phagocytosed cancer cells showed increased nuclear translocation of NF-KB, suggesting CAR-mediated intracellular signaling. To assess functionality in a more physiologically relevant context, we used tumor spheroids embedded in a dense 3D collagen matrix. Confocal microscopy and live-cell imaging revealed that CAR-MacCD34 cells efficiently migrated toward, and infiltrated tumor spheroids compared to untransduced MacCD34 cells. In addition, multiple tumor cell phagocytosis events mediated by CAR-MacCD34 cells were observed within the 3D model. We further evaluated the anti-tumor activity of CAR-MacCD34 cells in zebrafish larvae models of HER2+ tumors. Our results showed that CAR-MacCD34 cells persisted for over 8 days post-injection and promoted a significant reduction in tumor burden compared to untransduced MacCD34 cells. Conclusions: Collectively, our findings support a novel CAR-macrophage therapeutic approach with promising clinical potential, based on a renewable and accessible cellular source. Optimizing CAR-MacCD34 functionality in combination with existing therapies may contribute to durable anti-tumor responses and improved control of tumors. This work was supported by FAPESP, CNPq and PRONON.",
  "abstract_shown": true,
  "affiliations": [
    "Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil",
    "Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil",
    "University of Pennsylvania, Philadelphia, Pennsylvania, United States",
    "Disciplina de Obstetricia, Departamento de Obstetricia e Ginecologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil",
    "Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, SP, Brazil"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ian OVIDER"
    },
    {
      "affs": [
        0
      ],
      "name": "Livia FURQUIM"
    },
    {
      "affs": [
        0
      ],
      "name": "Carla FOGOLIN"
    },
    {
      "affs": [
        1
      ],
      "name": "Leonel JUNIOR"
    },
    {
      "affs": [
        0
      ],
      "name": "Viviane DA SILVA"
    },
    {
      "affs": [
        2
      ],
      "name": "Akash MATHEW"
    },
    {
      "affs": [
        0
      ],
      "name": "Elisa MATSUMURA"
    },
    {
      "affs": [
        1
      ],
      "name": "Lucas SANTOS"
    },
    {
      "affs": [
        0
      ],
      "name": "Vinicius PEREIRA"
    },
    {
      "affs": [
        0
      ],
      "name": "Gabriela EVANGELISTA"
    },
    {
      "affs": [
        0
      ],
      "name": "Theo DE OLIVEIRA"
    },
    {
      "affs": [
        0
      ],
      "name": "Samuel CAMPANELLI"
    },
    {
      "affs": [
        3
      ],
      "name": "Rossana FRANCISCO"
    },
    {
      "affs": [
        4
      ],
      "name": "Adriana PAES LEME"
    },
    {
      "affs": [
        1
      ],
      "name": "Tarcio BRAGA"
    },
    {
      "affs": [
        0
      ],
      "name": "Rafael ALMEIDA"
    },
    {
      "affs": [
        2
      ],
      "name": "Guilherme NADER"
    },
    {
      "affs": [
        0
      ],
      "name": "Vanderson ROCHA"
    },
    {
      "affs": [
        0
      ],
      "name": "Rodrigo Nalio RAMOS"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/16mc8rp6jhkwx.bib",
  "cited_by": 0,
  "doi": "10.1016/j.htct.2026.106833",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2531137926005808",
  "id": "16mc8rp6jhkwx",
  "issns": [
    "2531-1379",
    "2531-1387"
  ],
  "landing_url": "https://doi.org/10.1016/j.htct.2026.106833",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC633-647.5"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7223145633",
  "pdf_url": "https://www.sciencedirect.com/science/article/pii/S2531137926005808/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/16mc8rp6jhkwx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "03f8c1510ccb473995e229abdc5e0c9f",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.htct.2026.106833"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "CAR-ENGINEERED HUMAN HEMATOPOIETIC STEM CELL MACROPHAGES AS AN INNOVATIVE PLATFORM FOR TUMOR CONTROL",
  "title_text": "CAR-ENGINEERED HUMAN HEMATOPOIETIC STEM CELL MACROPHAGES AS AN INNOVATIVE PLATFORM FOR TUMOR CONTROL",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:24Z",
  "url": "https://research.draconitic.com/paper/16mc8rp6jhkwx",
  "venue": "Hematology, Transfusion and Cell Therapy",
  "versions": []
}