{
  "abstract": "Background: Atezolizumab plus bevacizumab is a first-line therapy for advanced hepatocellular carcinoma (HCC), yet only a subset of patients achieve durable benefit. The spatial organization of the tumour microenvironment (TME) and its relationship to immunotherapy response remain incompletely understood. Methods: We integrated single-cell transcriptomics, spatial transcriptomics, spatial proteomics, and bulk RNA-sequencing cohorts to characterize spatially organized immune ecosystems associated with immunotherapy response in HCC. Single-cell RNA sequencing from 100 HCC samples was used to construct a cellular reference, which was integrated with spatial transcriptomics from 12 sections to identify nine consensus spatial niches. Results: Niche 9 represented a lymphoid-enriched immune state characterized by B cells, plasma cells, natural killer cells, T-cell subsets, macrophages, and tertiary lymphoid structure-associated transcriptional features. Independent validation in a pretreatment, response-annotated Visium cohort showed enrichment of Niche 9-associated transcriptional activity in immunotherapy responders, while spatially co-registered 51-plex CODEX profiling provided orthogonal protein-level support for its lymphoid and immune-enriched phenotype. Multi-omics characterization further revealed coordinated immune-cell localization, ligand–receptor-associated patterns, and distinct metabolic programmes, with MEI1-positive plasma cells displaying enhanced secretory and stress-adaptation states. A nine-gene transcriptional signature derived from Niche 9 was associated with atezolizumab-plus-bevacizumab response, enhanced lymphoid immune features, lower Tumour Immune Dysfunction and Exclusion scores, and favourable clinical outcomes in independent cohorts. Conclusions: These multi-cohort and multi-omics analyses define a spatially derived lymphoid-enriched immune programme and link its molecular features to immunotherapy sensitivity in HCC.",
  "abstract_shown": true,
  "affiliations": [
    "Jiangxi Province Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China",
    "Queen Mary School, Nanchang University, Nanchang 330031, China",
    "College of Life Science, Jiangxi Science and Technology Normal University, Nanchang 330032, China",
    "Hepatobiliary Surgery, Department of General Surgery, Cancer Metastasis Institute, Huashan Hospital, Fudan University, Shanghai 200437, China",
    "The First Clinical Medical College, Nanchang University, Nanchang 330031, China",
    "The Second Clinical Medical College, Nanchang University, Nanchang 330031, China",
    "Jiangxi Provincial People’s Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang 330006, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Mingxiu Cai"
    },
    {
      "affs": [
        1
      ],
      "name": "Kaiheng Hu",
      "orcid": "0009-0003-7313-9222"
    },
    {
      "affs": [
        1
      ],
      "name": "Haichang Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Jing Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Yiqi Wu"
    },
    {
      "affs": [
        1
      ],
      "name": "Qirui Han"
    },
    {
      "affs": [
        3
      ],
      "name": "Jixuan Chen"
    },
    {
      "affs": [
        4
      ],
      "name": "Wei Zhong"
    },
    {
      "affs": [
        5
      ],
      "name": "Xiangfan Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Fangyuan Ding"
    },
    {
      "affs": [
        6
      ],
      "name": "Yuan Du"
    },
    {
      "affs": [
        1
      ],
      "name": "Yiming Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Feng Zhang",
      "orcid": "0000-0003-2723-4037"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0xy4jdgnhjgef.bib",
  "cited_by": 0,
  "doi": "10.3390/cancers18213442",
  "fulltext_url": null,
  "id": "0xy4jdgnhjgef",
  "issns": [
    "2072-6694"
  ],
  "landing_url": "https://www.mdpi.com/2072-6694/18/21/3442",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7223672229",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/0xy4jdgnhjgef.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:58Z",
      "native_id": "10.3390/cancers18213442",
      "source": "crossref",
      "url": "https://www.mdpi.com/2072-6694/18/21/3442"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "A Lymphoid-Enriched Spatial Immune Niche Defines an Immunotherapy-Responsive State in Hepatocellular Carcinoma",
  "title_text": "A Lymphoid-Enriched Spatial Immune Niche Defines an Immunotherapy-Responsive State in Hepatocellular Carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:58Z",
  "url": "https://research.draconitic.com/paper/0xy4jdgnhjgef",
  "venue": "Cancers",
  "versions": []
}