{
  "abstract": "γδ T-cell-based immunotherapies have become relevant as alternatives to conventional αβ T-cell products, with preclinical data demonstrating tumor burden reduction and the mitigation of tumor-induced tissue damage. Given that most CAR constructs have been optimized for αβ T cells, we hypothesized that distinct T-cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis of γδ and αβ T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although γδ and αβ CAR-T cells exhibit comparable levels of cytotoxicity, they differ phenotypically. Through a system-level phosphoproteomic analysis, we identified 307 phosphosites whose abundance differed between γδ and αβ CAR-T cells. Pathway enrichment analysis placed glycolysis/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. The results of functional validation studies confirmed that γδ CAR-T cells have lower glycolytic and oxidative phosphorylation capacity than αβ-CAR-T cells do and weaker activation of activator protein 1 (AP-1). Notably, we identified thioredoxin-interacting protein (TXNIP) as a potential actionable target to enhance γδ CAR-T-cell metabolism. Finally, we designed a new synthetic costimulatory receptor that potentiates AP-1 activation, resulting in improved in vivo persistence. These results highlight the fundamental biological differences between γδ and αβ T cells and support the development of cell type-specific receptor engineering strategies to maximize γδ CAR-T-cell function and therapeutic benefit.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL USA",
    "Proteomics & Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL USA",
    "Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL USA",
    "Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL USA",
    "Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiomar E. Bustos",
      "orcid": "0009-0004-2840-758X"
    },
    {
      "affs": [
        0
      ],
      "name": "Leticia Tordesillas"
    },
    {
      "affs": [
        0
      ],
      "name": "Elena Martinez Planes",
      "orcid": "0009-0006-3220-5395"
    },
    {
      "affs": [
        0
      ],
      "name": "Miguel G. Fontela",
      "orcid": "0000-0002-7563-3350"
    },
    {
      "affs": [
        0
      ],
      "name": "Sebastian Snedal"
    },
    {
      "affs": [
        0
      ],
      "name": "Renata Ariza Marques Rossetti"
    },
    {
      "affs": [
        1
      ],
      "name": "Victoria Izumi"
    },
    {
      "affs": [
        1
      ],
      "name": "Bin Fang"
    },
    {
      "affs": [
        2
      ],
      "name": "John M. Koomen",
      "orcid": "0000-0002-3818-1762"
    },
    {
      "affs": [
        3
      ],
      "name": "Eric A. Welsh"
    },
    {
      "affs": [
        4
      ],
      "name": "Patrick Hwu"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniel Abate-Daga",
      "orcid": "0000-0002-2571-0215"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2x8agn4gy86x1.bib",
  "cited_by": 1,
  "doi": "10.1038/s41423-026-01475-y",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723621/",
  "id": "2x8agn4gy86x1",
  "issns": [
    "1672-7681",
    "2042-0226"
  ],
  "landing_url": "https://doi.org/10.1038/s41423-026-01475-y",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7214705896",
  "pdf_url": "https://www.nature.com/articles/s41423-026-01475-y.pdf",
  "pmcid": "PMC13723621",
  "pmid": "42811126",
  "published": "2026-09-30",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/2x8agn4gy86x1.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:13Z",
      "native_id": "PMC13723621",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41423-026-01475-y"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells",
  "title_text": "CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:24Z",
  "url": "https://research.draconitic.com/paper/2x8agn4gy86x1",
  "venue": "Cellular and Molecular Immunology",
  "versions": []
}