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Peer-reviewedCC BY 4.0Cancers

A Lymphoid-Enriched Spatial Immune Niche Defines an Immunotherapy-Responsive State in Hepatocellular Carcinoma

  • Mingxiu Cai1,2
  • Kaiheng Hu2
  • Haichang Wang2
  • Jing Li3
  • Yiqi Wu2
  • Qirui Han2
  • Jixuan Chen4
  • Wei Zhong5
  • Xiangfan Huang6
  • Fangyuan Ding1
  • Yuan Du7
  • Yiming Liu2
1 more authors
  • Feng Zhang1
7 affiliations
  1. 1Jiangxi Province Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
  2. 2Queen Mary School, Nanchang University, Nanchang 330031, China
  3. 3College of Life Science, Jiangxi Science and Technology Normal University, Nanchang 330032, China
  4. 4Hepatobiliary Surgery, Department of General Surgery, Cancer Metastasis Institute, Huashan Hospital, Fudan University, Shanghai 200437, China
  5. 5The First Clinical Medical College, Nanchang University, Nanchang 330031, China
  6. 6The Second Clinical Medical College, Nanchang University, Nanchang 330031, China
  7. 7Jiangxi Provincial People’s Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang 330006, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{cai2026lymphoidenriched,
  title = {{A Lymphoid-Enriched Spatial Immune Niche Defines an Immunotherapy-Responsive State in Hepatocellular Carcinoma}},
  author = {Mingxiu Cai and Kaiheng Hu and Haichang Wang and Jing Li and Yiqi Wu and Qirui Han and Jixuan Chen and Wei Zhong and Xiangfan Huang and Fangyuan Ding and Yuan Du and Yiming Liu and Feng Zhang},
  journal = {Cancers},
  year = {2026},
  month = oct,
  doi = {10.3390/cancers18213442},
  url = {https://www.mdpi.com/2072-6694/18/21/3442},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A Lymphoid-Enriched Spatial Immune Niche Defines an Immunotherapy-Responsive State in Hepatocellular Carcinoma
AU  - Mingxiu Cai
AU  - Kaiheng Hu
AU  - Haichang Wang
AU  - Jing Li
AU  - Yiqi Wu
AU  - Qirui Han
AU  - Jixuan Chen
AU  - Wei Zhong
AU  - Xiangfan Huang
AU  - Fangyuan Ding
AU  - Yuan Du
AU  - Yiming Liu
AU  - Feng Zhang
PY  - 2026
DA  - 2026/10/24
JO  - Cancers
DO  - 10.3390/cancers18213442
UR  - https://www.mdpi.com/2072-6694/18/21/3442
AB  - 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.
SN  - 2072-6694
ER  -