{
  "abstract": "T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8+ T cells expressing an NY-ESO-1–specific T-cell receptor and subjected them to repeat tumor cell rechallenges. These screens revealed an enrichment of single-guide RNAs targeting components of cullin–RING E3 ubiquitin ligases, particularly cullin-5–RING E3 ligase (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors. Significance: The CRL5 complex negatively regulates CD8+ T-cell persistence during chronic antigen stimulation, identifying CRL5 disruption as a potential strategy to sustain T-cell effector function and improve ACT. See related commentary by Hanina and Maus, p. XX . See related article by Bachl et al., p. XX .",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA",
    "Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA, USA",
    "Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA",
    "Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA",
    "Dana Farber Cancer Institute, Harvard University, Cambridge, MA, USA",
    "Department Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany",
    "Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA",
    "Department of Medicine, University of California, San Francisco, San Francisco, CA, USA",
    "UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA",
    "Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA",
    "Department of Microbiology, Immunology and Medical Genetics, University of California Los Angeles, Los Angeles, CA, USA",
    "Department of Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Justin D. Saco"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daniel Karin"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "J.J. Patten"
    },
    {
      "affs": [
        2
      ],
      "name": "Stefanie Bachl"
    },
    {
      "affs": [
        2
      ],
      "name": "Carter Ching"
    },
    {
      "affs": [
        2
      ],
      "name": "Nupura Kale"
    },
    {
      "affs": [
        1
      ],
      "name": "Yichen Fan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Egmidio Medina"
    },
    {
      "affs": [
        1
      ],
      "name": "Nataly Naser Al Deen"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Ameya Champhekar"
    },
    {
      "affs": [
        4
      ],
      "name": "William G. Kaelin"
    },
    {
      "affs": [
        5
      ],
      "name": "Brenda A. Schulman"
    },
    {
      "affs": [
        1,
        3,
        6
      ],
      "name": "Katie M. Campbell"
    },
    {
      "affs": [
        6,
        7,
        8,
        9
      ],
      "name": "Julia Carnevale"
    },
    {
      "affs": [
        3,
        6,
        10,
        11
      ],
      "name": "Cristina Puig-Saus"
    },
    {
      "affs": [
        0,
        1,
        3,
        6,
        11
      ],
      "name": "Antoni Ribas"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9eqxz1dcbcjab.bib",
  "cited_by": 1,
  "doi": "10.1158/2326-6066.cir-26-0181",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13733672/",
  "id": "9eqxz1dcbcjab",
  "issns": [
    "2326-6066",
    "2326-6074"
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  "landing_url": "https://doi.org/10.1158/2326-6066.cir-26-0181",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
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      "2403|T-cell and B-cell Immunology"
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  "pdf_url": null,
  "pmcid": "PMC13733672",
  "pmid": "42878659",
  "published": "2026-10-15",
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  "ris": "https://research.draconitic.com/paper/9eqxz1dcbcjab.ris",
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      "first_seen": "2026-11-08T12:23:23Z",
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    {
      "field": "biology",
      "origin": "openalex:2403|T-cell and B-cell Immunology",
      "subfield": "immunology"
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  ],
  "title": "Cullin-5 RING E3 ligase limits CD8+ T-cell persistence and effector responses during chronic antigen stimulation",
  "title_text": "Cullin-5 RING E3 ligase limits CD8+ T-cell persistence and effector responses during chronic antigen stimulation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:23:23Z",
  "url": "https://research.draconitic.com/paper/9eqxz1dcbcjab",
  "venue": "Cancer immunology research",
  "versions": []
}