Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches

  • Cancer Cell. 2025 Sep 25:S1535-6108(25)00393-9. doi: 10.1016/j.ccell.2025.09.001.
Xiongfeng Chen  1 ,  Zhuan Zhou  1 ,  Luyu Xie  2 ,  Kailiang Qiao  3 ,  Yiyue Jia  1 ,  Shunheng Liu  4 ,  Zeynep Yazgan  4 ,  Francesca Rossi  5 ,  Yang Liu  6 ,  Bo Zhang  6 ,  Patricio M Polanco  5 ,  Herbert J Zeh 3rd  5 ,  Alex C Kim  7 ,  Huocong Huang  8
Affiliations
  • 1. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 8. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 41005303 DOI: 10.1016/j.ccell.2025.09.001
Abstract

Recent studies identify a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain poorly understood. To gain a comprehensive understanding of the origin and function of apCAFs, we construct a fibroblast molecular atlas across 15 types of tissues and solid tumors. Our integration study unexpectedly reveals two distinct apCAF populations present in most Cancer types: one associated with mesothelial-like cells and the Other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF populations. We find that mesothelial-like apCAFs are located near Cancer cells, while fibrocyte-like apCAFs are associated with lymphocyte-enriched niches. Additionally, we discovered that both apCAF populations can up-regulate secreted phosphoprotein 1 (SPP1), which facilitates primary tumor formation, peritoneal metastasis, and therapy resistance. Taken together, this study offers an unprecedented resolution in analyzing apCAFs and their spatial niches.

Keywords
cancer-associated fibroblast; fibrocyte; mesothelial cell; pancreatic cancer; peritoneal metastasis.
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