{
  "abstract": "NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor-immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 32,
  "authors": [
    {
      "name": "K. Nishimura"
    },
    {
      "name": "R. Maenosono"
    },
    {
      "name": "T. Owari"
    },
    {
      "name": "M. Sakamoto"
    },
    {
      "name": "T. Nishino"
    },
    {
      "name": "K. Hirosuna"
    },
    {
      "name": "T. Tsujino"
    },
    {
      "name": "T. Izumi-Tamura"
    },
    {
      "name": "Y. Yoshikawa"
    },
    {
      "name": "M. Azuma"
    },
    {
      "name": "S. Inoue"
    },
    {
      "name": "A. Kawachi"
    },
    {
      "name": "A. Ishida"
    },
    {
      "name": "K. Nishimori"
    },
    {
      "name": "J. Mukohyama"
    },
    {
      "name": "N. Shinohara"
    },
    {
      "name": "M. Sakumoto"
    },
    {
      "name": "M. Amisaki"
    },
    {
      "name": "K. Okuyama"
    },
    {
      "name": "M. Ishida"
    },
    {
      "name": "M. Ajiro"
    },
    {
      "name": "Y. Hirose"
    },
    {
      "name": "Y. Suzuki"
    },
    {
      "name": "H. Nishikawa"
    },
    {
      "name": "H. Azuma"
    },
    {
      "name": "F. L. F. Carvalho"
    },
    {
      "name": "A. S. Kibel"
    },
    {
      "name": "L. Jia"
    },
    {
      "name": "S. Koyama"
    },
    {
      "name": "T. Yoshino"
    },
    {
      "name": "K. Komura"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Yoshimi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dzshmeahbm8q1.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.757381",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1.full",
  "id": "dzshmeahbm8q1",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1",
  "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",
      "cancer biology"
    ],
    [
      "openalex",
      "2746|Bladder and Urothelial Cancer Treatments"
    ]
  ],
  "openalex": "W7221115491",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dzshmeahbm8q1.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:53Z",
      "native_id": "10.64898/2026.10.07.757381",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer",
  "title_text": "NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:53Z",
  "url": "https://research.draconitic.com/paper/dzshmeahbm8q1",
  "venue": "bioRxiv",
  "versions": []
}