{
  "abstract": "Multicellular programs in the tumour microenvironment (TME) drive cancer pathogenesis and response to therapy but remain challenging to identify and profile clinically1–3. Here, we present a machine-learning framework for multi-analyte profiling of spatially dependent cell states and multicellular ecosystems, termed spatial ecotypes (SEs). By integrating over 10 million single-cell and spot-level spatial transcriptomes from diverse human carcinomas and melanomas, we identified nine SEs with broad conservation, each of which has unique biology, geospatial features and clinical outcome associations, including several linked to immunotherapy response. Notably, SEs were distinguishable by DNA methylation profiling and were recoverable from plasma cell-free DNA (cfDNA) using deep learning. In cfDNA from nearly 100 patients with melanoma, SE levels exhibited striking associations with immunotherapy response. Our data reveal fundamental units of TME organization and demonstrate a multimodal platform for profiling solid and liquid TMEs, with implications for improved risk stratification and therapy personalization. Multimodal machine learning reveals that tumour microenvironments can be decomposed into spatially organized multicellular ecosystems, termed spatial ecotypes, that can be accessed non-invasively via liquid biopsy and used to profile individual cancers and target treatments.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biomedical Data Science, Stanford University, Stanford, CA, USA",
    "Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA",
    "Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA",
    "Department of Computer Science, Stanford University, Stanford, CA, USA",
    "Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA",
    "Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway",
    "Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway",
    "Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway",
    "Department of Computer Science and Engineering, Washington University, St. Louis, MO, USA",
    "Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA",
    "Department of Medicine, Clement J. Zablocki VA Medical Center, Milwaukee, WI, USA",
    "Division of Endocrinology and Molecular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA",
    "Department of Bioengineering, Stanford University, Stanford, CA, USA",
    "Department of Systems Biology, Columbia University, New York, NY, USA",
    "Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA",
    "Stanford Cancer Institute, Stanford University, Stanford, CA, USA",
    "Yale Center for Genome Analysis, Department of Molecular Biophysics and Biochemistry, Institute for Biomolecular Design and Discovery, Yale University, New Haven, CT, USA",
    "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA",
    "Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA",
    "Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA",
    "Department of Surgery, University of Rochester School of Medicine, Rochester, NY, USA",
    "Department of Medicine, Division of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA",
    "Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA",
    "Division of Dermatology, Washington University School of Medicine, St. Louis, MO, USA",
    "Department of Computer Science and Engineering, Washington University, St. Louis, MO, USA. Chaudhuri.Aadel@mayo.edu",
    "Department of Immunology, Mayo Clinic, Rochester, MN, USA. Chaudhuri.Aadel@mayo.edu",
    "Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. Chaudhuri.Aadel@mayo.edu",
    "Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. Chaudhuri.Aadel@mayo.edu",
    "Chan Zuckerberg Biohub - San Francisco, San Francisco, CA, USA. amnewman@stanford.edu",
    "Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. amnewman@stanford.edu",
    "Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. amnewman@stanford.edu",
    "Stanford Cancer Institute, Stanford University, Stanford, CA, USA. amnewman@stanford.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 29,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Wubing Zhang",
      "orcid": "0000-0003-2233-299X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Erin L. Brown",
      "orcid": "0000-0002-0004-3487"
    },
    {
      "affs": [
        2
      ],
      "name": "Abul Usmani",
      "orcid": "0000-0001-5485-7323"
    },
    {
      "affs": [
        2
      ],
      "name": "Noah J. Earland",
      "orcid": "0000-0003-0170-407X"
    },
    {
      "affs": [
        0,
        3,
        1
      ],
      "name": "Minji Kang",
      "orcid": "0000-0003-0009-4249"
    },
    {
      "affs": [
        4
      ],
      "name": "Chibuzor Olelewe"
    },
    {
      "affs": [
        4
      ],
      "name": "Anushka Viswanathan",
      "orcid": "0009-0004-8140-8936"
    },
    {
      "affs": [
        4
      ],
      "name": "Pradeep S. Chauhan",
      "orcid": "0000-0003-4304-011X"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Chloé Beate Steen",
      "orcid": "0000-0001-7290-7128"
    },
    {
      "affs": [
        3
      ],
      "name": "Hyun Soo Jeon",
      "orcid": "0000-0001-8388-2480"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Susanna Avagyan",
      "orcid": "0009-0003-1876-157X"
    },
    {
      "affs": [
        8,
        4
      ],
      "name": "Irfan Alahi",
      "orcid": "0009-0008-4577-3548"
    },
    {
      "affs": [
        9,
        10,
        11
      ],
      "name": "Nicholas P. Semenkovich",
      "orcid": "0000-0001-5266-6734"
    },
    {
      "affs": [
        12,
        0,
        1
      ],
      "name": "Janella C. Schwab",
      "orcid": "0000-0003-3784-9174"
    },
    {
      "affs": [
        2
      ],
      "name": "Chloe M. Sachs"
    },
    {
      "affs": [
        4
      ],
      "name": "Faridi Qaium",
      "orcid": "0009-0007-0640-5905"
    },
    {
      "affs": [
        2
      ],
      "name": "Peter K. W. Harris",
      "orcid": "0000-0003-1557-1722"
    },
    {
      "affs": [
        13
      ],
      "name": "Qingyuan Cai",
      "orcid": "0009-0000-9391-2305"
    },
    {
      "affs": [
        0,
        14,
        15
      ],
      "name": "Andrew J. Gentles",
      "orcid": "0000-0002-0941-9858"
    },
    {
      "affs": [
        16
      ],
      "name": "James Knight"
    },
    {
      "affs": [
        17
      ],
      "name": "Rondell P. Graham",
      "orcid": "0000-0002-8686-4867"
    },
    {
      "affs": [
        18
      ],
      "name": "Antonietta Bacchiocchi"
    },
    {
      "affs": [
        17,
        19
      ],
      "name": "Peter C. Lucas",
      "orcid": "0000-0003-4880-7172"
    },
    {
      "affs": [
        20
      ],
      "name": "Ryan Courtney Fields",
      "orcid": "0000-0001-6176-8943"
    },
    {
      "affs": [
        21,
        22
      ],
      "name": "Mario Sznol",
      "orcid": "0000-0003-4137-9662"
    },
    {
      "affs": [
        18,
        22
      ],
      "name": "Ruth Halaban",
      "orcid": "0000-0001-8451-1964"
    },
    {
      "affs": [
        23
      ],
      "name": "Di Chen",
      "orcid": "0000-0001-9509-2814"
    },
    {
      "affs": [
        24,
        25,
        26,
        27
      ],
      "name": "Aadel A. Chaudhuri",
      "orcid": "0000-0003-3115-3061"
    },
    {
      "affs": [
        28,
        29,
        30,
        31
      ],
      "name": "Aaron M. Newman",
      "orcid": "0000-0002-1857-8172"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8hx6hg38p1tw0.bib",
  "cited_by": 31,
  "doi": "10.1038/s41586-026-10452-4",
  "fulltext_url": null,
  "id": "8hx6hg38p1tw0",
  "issns": [
    "0028-0836",
    "1476-4687"
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  "landing_url": "https://doi.org/10.1038/s41586-026-10452-4",
  "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/",
  "metadata_licence": null,
  "native_subjects": [
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      "1312|Single-cell and spatial transcriptomics"
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  "openalex": "W7160390722",
  "pdf_url": null,
  "pmcid": "PMC13293879",
  "pmid": "42092150",
  "published": "2026-05-06",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/8hx6hg38p1tw0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:46Z",
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      "url": "https://doi.org/10.1038/s41586-026-10452-4"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Single-cell and spatial transcriptomics",
      "subfield": "molecular-biology"
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  ],
  "title": "Non-invasive profiling of the tumour microenvironment with spatial ecotypes",
  "title_text": "Non-invasive profiling of the tumour microenvironment with spatial ecotypes",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T13:20:37Z",
  "url": "https://research.draconitic.com/paper/8hx6hg38p1tw0",
  "venue": "Nature",
  "versions": []
}