{
  "abstract": "Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers but has shown limited efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). The cellular and molecular factors that influence CAR T cell therapy response remain largely unknown. By integrating modular in vivo CRISPR screens with single-cell genomics and immunocompetent orthotopic models of PDAC, we uncover oxidative and proteotoxic stress pathways as previously unknown modulators of CAR T cell therapy response. Disruption of stress regulatory genes, particularly Keap1 and Slc33a1 , sensitizes PDAC tumors to CAR T cell killing in vivo. Hyperactivation of the Nrf2 pathway by genetic ablation of Keap1 or endogenous engineering of clinically observed Keap1 or Nfe2l2 mutations enhances tumor susceptibility to CAR T cell therapy. Thus, tumor-intrinsic molecular stress phenotypes can induce unexpected cell state–specific vulnerabilities to cell-based immunotherapies. These findings provide a foundation to improve efficacy of CAR T cell therapy in solid malignancies and to better stratify patients with cancer by tumor genotype.",
  "abstract_shown": true,
  "affiliations": [
    "The David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02142, USA.",
    "Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.",
    "Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.",
    "David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Julia Fröse",
      "orcid": "0000-0002-8179-1777"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Evelyn Chen",
      "orcid": "0000-0003-1102-6997"
    },
    {
      "affs": [
        0
      ],
      "name": "Charles A. Whittaker",
      "orcid": "0000-0002-2400-0094"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Paul Leclerc",
      "orcid": "0009-0007-6392-6512"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sean Doherty",
      "orcid": "0009-0007-2096-8026"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Adam Langenbucher"
    },
    {
      "affs": [
        0
      ],
      "name": "Jasmine Shao",
      "orcid": "0009-0004-6831-9832"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Riley D. Hellinger",
      "orcid": "0000-0001-6303-3641"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daniel Goulet"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Tuomas Tammela",
      "orcid": "0000-0003-3675-6961"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Francisco J. Sánchez-Rivera",
      "orcid": "0000-0002-8466-8563"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Michael T. Hemann",
      "orcid": "0000-0001-6776-2163"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7fb2rwmd77t3q.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aeh8973",
  "fulltext_url": null,
  "id": "7fb2rwmd77t3q",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aeh8973",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7216116112",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/7fb2rwmd77t3q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aeh8973",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aeh8973"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Tumor cell–intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer",
  "title_text": "Tumor cell–intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/7fb2rwmd77t3q",
  "venue": "Science Advances",
  "versions": []
}