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Peer-reviewedCC BY-NC-NDMolecular cancer

Single-cell profiling defines cellular ecosystems and malignant cell state coupling across pan-cancer tumor microenvironments.

  • Xiaoxiao Yang1
  • Yang Tong2,3
  • Yuting Wang1,4
  • Peng Xie5
  • Xin Li6
  • Jiapei Yuan7,8
  • Yang Yang9,10
10 affiliations
  1. 1The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, The Second Hospital of Tianjin Medical University, Tianjin Key Laboratory of Inflammatory Biology, Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  2. 2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.
  3. 3Tianjin Institutes of Health Science, Tianjin, 301600, China.
  4. 4Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  5. 5State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China.
  6. 6Department of Geriatrics, The Second Hospital of Tianjin Medical University, Tianjin Interdisciplinary Innovation Centre for Health and Meteorology, Tianjin, 300211, China. [email protected].
  7. 7State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China. [email protected].
  8. 8Tianjin Institutes of Health Science, Tianjin, 301600, China. [email protected].
  9. 9The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, The Second Hospital of Tianjin Medical University, Tianjin Key Laboratory of Inflammatory Biology, Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. [email protected].
  10. 10Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. [email protected].
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Abstract

Tumors are embedded within complex microenvironments composed of malignant, immune and stromal cells, yet how coordinated cellular organization shapes tumor biology across cancers remains incompletely understood. Here we integrate single-cell transcriptomic profiles from over two million cells spanning 19 human epithelial cancers to construct a comprehensive pan-cancer atlas of tumor microenvironment (TME) organization. We identify cell subsets selectively enriched in tumors compared with normal tissues and show that their relative abundance is associated with clinical outcomes. By clustering tumors according to their cellular composition, we define eight recurrent cellular ecosystem subtypes that capture coordinated variation in immune and stromal architectures across cancer types. Comparative analyses reveal that these ecosystem states are associated with distinct tumor-intrinsic molecular programs, including differences in signaling pathway activity, transcriptional regulation and copy number alterations. We further uncover subtype-specific patterns of ligand-receptor interactions linking malignant cells with immune and stromal compartments and provide independent spatial support for these interactions using spatial transcriptomic data. Together, this work provides a unified framework for tumor ecosystem stratification and highlights cellular organization as a key dimension of tumor heterogeneity with potential implications for precision cancer therapy.

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Cite

BibTeXRIS
BibTeX
@article{yang2026singlecell,
  title = {{Single-cell profiling defines cellular ecosystems and malignant cell state coupling across pan-cancer tumor microenvironments.}},
  author = {Xiaoxiao Yang and Yang Tong and Yuting Wang and Peng Xie and Xin Li and Jiapei Yuan and Yang Yang},
  journal = {Molecular cancer},
  year = {2026},
  month = jul,
  doi = {10.1186/s12943-026-02741-3},
  url = {https://europepmc.org/article/MED/42907887},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Single-cell profiling defines cellular ecosystems and malignant cell state coupling across pan-cancer tumor microenvironments.
AU  - Xiaoxiao Yang
AU  - Yang Tong
AU  - Yuting Wang
AU  - Peng Xie
AU  - Xin Li
AU  - Jiapei Yuan
AU  - Yang Yang
PY  - 2026
DA  - 2026/07/01
JO  - Molecular cancer
DO  - 10.1186/s12943-026-02741-3
UR  - https://europepmc.org/article/MED/42907887
AB  - Tumors are embedded within complex microenvironments composed of malignant, immune and stromal cells, yet how coordinated cellular organization shapes tumor biology across cancers remains incompletely understood. Here we integrate single-cell transcriptomic profiles from over two million cells spanning 19 human epithelial cancers to construct a comprehensive pan-cancer atlas of tumor microenvironment (TME) organization. We identify cell subsets selectively enriched in tumors compared with normal tissues and show that their relative abundance is associated with clinical outcomes. By clustering tumors according to their cellular composition, we define eight recurrent cellular ecosystem subtypes that capture coordinated variation in immune and stromal architectures across cancer types. Comparative analyses reveal that these ecosystem states are associated with distinct tumor-intrinsic molecular programs, including differences in signaling pathway activity, transcriptional regulation and copy number alterations. We further uncover subtype-specific patterns of ligand-receptor interactions linking malignant cells with immune and stromal compartments and provide independent spatial support for these interactions using spatial transcriptomic data. Together, this work provides a unified framework for tumor ecosystem stratification and highlights cellular organization as a key dimension of tumor heterogeneity with potential implications for precision cancer therapy.
SN  - 1476-4598
ER  -