{
  "abstract": "Background Immune checkpoint blockade (ICB) therapy has demonstrated remarkable efficacy in microsatellite instability–high (MSI-H) gastrointestinal cancers, yet the determinants of sustained therapeutic response vs resistance remain poorly understood.Methods To comprehensively characterize the spatial architecture and transcriptional programs of tumors achieving sustained complete response (CR) versus those with non-sustained response (NR). We generated spatially resolved transcriptomic profiles from 18 tumor specimens obtained from 13 patients with gastrointestinal cancer, including 11 MSI-H and 2 microsatellite stable cases, with paired tissues collected before and after ICB therapy.Results Tumor cell meta-programs (MPs) exhibited distinct spatial gradients associated with response. The epithelial–mesenchymal transition MP was enriched at the invasive margin of pre- and post-NR tumors and diminished toward the core, while the cycling–high-interferon MP peaked at the periphery of pre-CR tumors. In pre-CR tumors, malignant cells co-localized with B cells and T follicular helper cells within tertiary lymphoid structures (TLSs), whereas in pre- and post-NR tumors, they were associated with macrophages and cancer-associated fibroblasts. Notably, TLSs in CR tumors exhibited stronger immune activation signatures irrespective of their maturation state. Cell–cell communication analysis further revealed immune activation at the tumor–stroma interface in CR tumors, contrasting with immunosuppressive signaling in NR tumors.Conclusions Our study reveals distinct spatial and transcriptional programs underlying differential responses to ICB in MSI-H gastrointestinal cancers, highlighting the pivotal role of tumor–immune–stromal organization and interaction in shaping therapeutic outcomes. These findings provide a framework for predicting response to better stratify patients and guiding future strategies to enhance immunotherapy efficacy.",
  "abstract_shown": true,
  "affiliations": [
    "Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, USA",
    "Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA",
    "Center for Integrated Cancer Architecture, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 28,
  "authors": [
    {
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        0
      ],
      "name": "Xueshuai Han",
      "orcid": "0000-0002-9931-0150"
    },
    {
      "affs": [
        1
      ],
      "name": "Kohei Yamashita"
    },
    {
      "affs": [
        1
      ],
      "name": "Melissa Pool Pizzi"
    },
    {
      "affs": [
        0
      ],
      "name": "Kyung Serk Cho"
    },
    {
      "affs": [
        0
      ],
      "name": "Enyu Dai"
    },
    {
      "affs": [
        0
      ],
      "name": "Yunhe Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Kai Yu"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Yibo Dai"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Fuduan Peng"
    },
    {
      "affs": [
        0
      ],
      "name": "Guangsheng Pei"
    },
    {
      "affs": [
        0
      ],
      "name": "Tian Chu"
    },
    {
      "affs": [
        1
      ],
      "name": "Matheus Sewastjanow-Silva",
      "orcid": "0000-0003-4804-1891"
    },
    {
      "affs": [
        1
      ],
      "name": "Katsuhiro Yoshimura"
    },
    {
      "affs": [
        1
      ],
      "name": "Yibo Fan"
    },
    {
      "affs": [
        3
      ],
      "name": "Rebecca E Waters"
    },
    {
      "affs": [
        3
      ],
      "name": "Qiong Gan"
    },
    {
      "affs": [
        3
      ],
      "name": "Feng Yin"
    },
    {
      "affs": [
        1
      ],
      "name": "Shilpa S Dhar"
    },
    {
      "affs": [
        1
      ],
      "name": "Isadora Guimaraes Martins"
    },
    {
      "affs": [
        1
      ],
      "name": "Jason Willis"
    },
    {
      "affs": [
        1
      ],
      "name": "Mariela Blum Murphy"
    },
    {
      "affs": [
        1
      ],
      "name": "Jenny J Li"
    },
    {
      "affs": [
        4
      ],
      "name": "Brian D Badgwell"
    },
    {
      "affs": [
        1
      ],
      "name": "Van K Morris"
    },
    {
      "affs": [
        1
      ],
      "name": "Michael J Overman",
      "orcid": "0000-0001-5377-135X"
    },
    {
      "affs": [
        0,
        2,
        5,
        6,
        7
      ],
      "name": "Linghua Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Jaffer A Ajani"
    }
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  "bibtex": "https://research.draconitic.com/paper/3ed2d55j9qaac.bib",
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  "doi": "10.1136/jitc-2026-015653",
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  "language": "en",
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      "heading",
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  "pmcid": "PMC13723904",
  "pmid": "42951311",
  "published": "2026-10-28",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/3ed2d55j9qaac.ris",
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  "title": "Spatial architecture of the tumor–stroma interface and transcriptional programs shape immunotherapy response in MSI-H gastrointestinal cancers",
  "title_text": "Spatial architecture of the tumor–stroma interface and transcriptional programs shape immunotherapy response in MSI-H gastrointestinal cancers",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T12:22:27Z",
  "url": "https://research.draconitic.com/paper/3ed2d55j9qaac",
  "venue": "Journal for ImmunoTherapy of Cancer",
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}