{
  "abstract": "Glypican-3 (GPC3) is a promising target in adoptive T-cell therapy for hepatocellular carcinoma (HCC). TCR-A and TCR-B are two recently identified GPC3-specific TCRs recognizing the same HLA-A*02:01-restricted epitope but displaying markedly different therapeutic efficacy. To define the determinants of productive TCR-antigen recognition, we integrated high-resolution structures of both binary pMHC and ternary TCR:pMHC complexes, biolayer interferometry, peptide mutagenesis, target-cell conjugation assays, repetitive antigen challenge (RAC) and in vivo models. Structurally, conformational permissiveness of the immunodominant GPC3(522-530) peptide within HLA-A*02:01's groove is central for productive TCR docking, with TCR-B presenting slower association but prolonged dwell time. Functional divergence emerged during target-cell engagement and amplified under RAC conditions, where TCR-B sustained cytotoxic activity while TCR-A progressively lost function. This superior functional endurance translated into complete tumor eradication and durable responses in vivo. These findings provide a mechanistic basis and a conceptual framework for the selection and optimization of TCRs for adoptive immunotherapy.",
  "abstract_shown": true,
  "affiliations": [
    "Navarrabiomed"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "L. Oyon-Olea"
    },
    {
      "name": "E. Vercher"
    },
    {
      "name": "G. Dichiara-Rodriguez"
    },
    {
      "name": "E. Erausquin"
    },
    {
      "name": "S. Hervas-Stubbs"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Lopez-Sagaseta"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ay29tx8544kz2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.15.750028",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1.full",
  "id": "ay29tx8544kz2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7213904249",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ay29tx8544kz2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:29Z",
      "native_id": "10.64898/2026.09.15.750028",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.15.750028v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy",
  "title_text": "Structure-function profiling identifies determinants of TCR-T cell therapeutic efficacy",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:29Z",
  "url": "https://research.draconitic.com/paper/ay29tx8544kz2",
  "venue": "bioRxiv",
  "versions": []
}