{
  "abstract": "Adoptive T-cell therapies using chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) have transformed cancer treatment but remain limited by poor persistence and progressive T-cell exhaustion. Manufacturing strategies that promote memory T-cell formation may improve therapeutic durability. Here we investigated whether transient pharmacologic activation of the p53 pathway influences the differentiation and function of human CD8+ T cells. p53 expression was minimal in quiescent naïve CD8+ T cells but was rapidly induced following T-cell receptor activation. Pharmacologic inhibition of the p53 negative regulator MDM2 increased p53 protein levels and promoted expansion of central memory and stem-like memory T-cell subsets during clonal proliferation. Treated cells displayed enhanced mitochondrial fitness, increased polyfunctional cytokine production, and transcriptional programs consistent with memory differentiation and reduced exhaustion. Importantly, TCR-engineered CD8+ T cells generated in the presence of the MDM2 inhibitor Navtemadlin demonstrated superior tumor-cell killing in vitro compared with conventionally manufactured cells. These findings identify transient p53 activation as a pharmacologic strategy to enhance memory programming during T-cell manufacturing and suggest a clinically feasible approach to improve the efficacy of adoptive T-cell immunotherapies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Surgery, UCLA",
    "Division of Surgical Oncology, UCLA",
    "Division of Hematology/Oncology, UCLA",
    "Department of Pediatrics, UCLA",
    "David Geffen School of Medicine, UCLA",
    "UCLA Bioengineering, UCLA",
    "Jonsson Comprehensive Cancer Center, Sarcoma Oncology Program, UCLA"
  ],
  "article_type": "brief report",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alexandra Boix de Jesus"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hy B. Dao"
    },
    {
      "affs": [
        0
      ],
      "name": "Anthony Imani"
    },
    {
      "affs": [
        2
      ],
      "name": "Gabriel A. Rodriguez"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Michael S. Shehata"
    },
    {
      "affs": [
        3
      ],
      "name": "Rachana R. Chandran"
    },
    {
      "affs": [
        4
      ],
      "name": "Stuart A. Fine"
    },
    {
      "affs": [
        4
      ],
      "name": "Sin Y. Lim"
    },
    {
      "affs": [
        0
      ],
      "name": "Michelle To"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Serena Y. Lofftus"
    },
    {
      "affs": [
        5
      ],
      "name": "Nicolas Pedroncelli"
    },
    {
      "affs": [
        0,
        1,
        6
      ],
      "name": "Fritz C. Eilber"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Brigitte N. Gomperts"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tyler R. McCaw"
    },
    {
      "affs": [
        0,
        1,
        6
      ],
      "name": "Cristina Puig-Saus"
    },
    {
      "affs": [
        0,
        1,
        6
      ],
      "name": "Joseph G. Crompton"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/58vrqx52jz2ck.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1910235",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719607/?tool=EBI",
  "id": "58vrqx52jz2ck",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1910235/full",
  "language": "eng",
  "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",
      "Brief Research Report"
    ],
    [
      "openalex",
      "2403|T-cell and B-cell Immunology"
    ]
  ],
  "openalex": "W7222498301",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1910235/pdf",
  "pmcid": "PMC13719607",
  "pmid": "42964330",
  "published": "2026-10-16",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/58vrqx52jz2ck.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1910235",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1910235/full"
    },
    {
      "first_seen": "2026-10-31T12:21:36Z",
      "native_id": "PMC:PMC13719607",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13719607"
    },
    {
      "first_seen": "2026-11-02T12:23:32Z",
      "native_id": "PMC13719607",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fimmu.2026.1910235"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|T-cell and B-cell Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells",
  "title_text": "p53 activation via pharmacologic MDM2 inhibition constrains exhaustion and enhances antitumor function of human CD8+ T cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:38Z",
  "url": "https://research.draconitic.com/paper/58vrqx52jz2ck",
  "venue": "Frontiers in Immunology",
  "versions": []
}