{
  "abstract": "Background: Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematologic malignancies; however, its efficacy against solid tumors remains limited due to the immunosuppressive tumor microenvironment. Enhancing CAR-T cell persistence and function through the use of culture media additives offers a potential strategy to overcome these challenges.\n\nMethods: We conducted a systematic evaluation of CAR-T cell culture media additives and selected five FDA-approved compounds—decitabine, palbociclib, metformin, enasidenib, and rapamycin—based on their diverse mechanisms of action and clinical safety profiles. Anti-mesothelin (MSLN) CAR-T cells were generated and assessed under hypoxic in vitro conditions and in two subcutaneous solid tumor mouse models. The effects of individual and combinatorial additive treatments on CAR-T cell function were evaluated. To elucidate the underlying mechanisms, we performed RNA sequencing and metabolic analyses.\n\nResults: All five additives partially reversed hypoxia-induced dysfunction in CAR-T cells, with palbociclib, enasidenib, and rapamycin demonstrating the most significant enhancement of cytotoxicity in both 2D and 3D assays. Notably, the combination of palbociclib and rapamycin (Pal + Rap) yielded pronounced additive improvements in CAR-T function, markedly enhancing CAR-T cell persistence, tumor-killing activity, and resistance to tumor recurrence in both HCC1806 and Capan-2 xenograft models. Transcriptomic and metabolic profiling showed concurrent upregulation of oxidative phosphorylation and improved in vivo anti-tumor function in Pal + Rap-preconditioned hypoxic CAR-T cells.\n\nConclusions: Preconditioning CAR-T cells with palbociclib and rapamycin enhances their metabolic fitness and anti-tumor efficacy under hypoxia, offering a simple and clinically feasible strategy to improve CAR-T therapy against solid tumors.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08749-z.",
  "abstract_shown": true,
  "affiliations": [
    "Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing, 210023 China",
    "Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, No. 23 Pingjiang Road Hexi District, Tianjin, 300211 China",
    "Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China",
    "Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010000 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Muya Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Lianfeng Zhao"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhiying Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenwen Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Luxia Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiaqi Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jinhua Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jialu Hong"
    },
    {
      "affs": [
        0
      ],
      "name": "Feiyan Pan"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhigang Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Lingfeng He"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhiqiang Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Tangfeng Lv"
    },
    {
      "affs": [
        3
      ],
      "name": "Xudong Ao"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhigang Guo",
      "orcid": "0000-0001-7771-1829"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1r3kjyy5qj1r9.bib",
  "cited_by": 0,
  "doi": "10.1186/s12967-026-08749-z",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737794/",
  "id": "1r3kjyy5qj1r9",
  "issns": [
    "1479-5876"
  ],
  "landing_url": "https://doi.org/10.1186/s12967-026-08749-z",
  "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",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7201833215",
  "pdf_url": null,
  "pmcid": "PMC13737794",
  "pmid": "42983439",
  "published": "2026-08-07",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/1r3kjyy5qj1r9.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:54Z",
      "native_id": "PMC13737794",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12967-026-08749-z"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Palbociclib and rapamycin pretreatment boosted the persistence and functionality of CAR-T cells in solid tumors through metabolic reprogramming",
  "title_text": "Palbociclib and rapamycin pretreatment boosted the persistence and functionality of CAR-T cells in solid tumors through metabolic reprogramming",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:54Z",
  "url": "https://research.draconitic.com/paper/1r3kjyy5qj1r9",
  "venue": "Journal of Translational Medicine",
  "versions": []
}