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Peer-reviewedCC BY-NC-NDCancer Cell

Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts

  • Yunhe Liu1
  • Xiongfeng Chen2
  • Yibo Dai3
  • Yiyue Jia2
  • Yann Kieffer4
  • Luyu Xie5
  • Zhuan Zhou2
  • Lauren A. Tyler2
  • Alex C. Kim2
  • Giulia Biffi6
  • Akshay T. Krishnamurty7
  • Fatima Mechta‐Grigoriou8
5 more authors
  • Ruth Scherz‐Shouval9
  • Mara H. Sherman10
  • Shannon J. Turley11
  • Linghua Wang
  • Huocong Huang12
12 affiliations
  1. 1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
  3. 3Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
  4. 4Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, Paris, France; Inserm, U1339, CNRS UMR3666, Paris, France
  5. 5Quantitative Biomedical Research Center, Department of Health Data Science and Biostatistics, Peter O'Donnell Jr School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
  6. 6Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK. Electronic address: [email protected]
  7. 7Genentech, South San Francisco, CA, USA. Electronic address: [email protected]
  8. 8Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, Paris, France; Inserm, U1339, CNRS UMR3666, Paris, France. Electronic address: [email protected]
  9. 9Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. Electronic address: [email protected]
  10. 10Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected]
  11. 11Amgen Inc., Thousand Oaks, CA, USA. Electronic address: [email protected]
  12. 12Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected]
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Abstract

Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.

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Cite

BibTeXRIS
BibTeX
@article{liu2026molecular,
  title = {{Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts}},
  author = {Yunhe Liu and Xiongfeng Chen and Yibo Dai and Yiyue Jia and Yann Kieffer and Luyu Xie and Zhuan Zhou and Lauren A. Tyler and Alex C. Kim and Giulia Biffi and Akshay T. Krishnamurty and Fatima Mechta‐Grigoriou and Ruth Scherz‐Shouval and Mara H. Sherman and Shannon J. Turley and Linghua Wang and Huocong Huang},
  journal = {Cancer Cell},
  year = {2026},
  month = jun,
  doi = {10.1016/j.ccell.2026.06.001},
  url = {https://doi.org/10.1016/j.ccell.2026.06.001},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts
AU  - Yunhe Liu
AU  - Xiongfeng Chen
AU  - Yibo Dai
AU  - Yiyue Jia
AU  - Yann Kieffer
AU  - Luyu Xie
AU  - Zhuan Zhou
AU  - Lauren A. Tyler
AU  - Alex C. Kim
AU  - Giulia Biffi
AU  - Akshay T. Krishnamurty
AU  - Fatima Mechta‐Grigoriou
AU  - Ruth Scherz‐Shouval
AU  - Mara H. Sherman
AU  - Shannon J. Turley
AU  - Linghua Wang
AU  - Huocong Huang
PY  - 2026
DA  - 2026/06/25
JO  - Cancer Cell
DO  - 10.1016/j.ccell.2026.06.001
UR  - https://doi.org/10.1016/j.ccell.2026.06.001
AB  - Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.
SN  - 1535-6108
SN  - 1878-3686
ER  -