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Background <p>Cancer-associated fibroblasts (CAFs) are increasingly recognized as critical contributors to the limited efficacy of immunotherapy, particularly through the establishment of immune-excluded tumor microenvironments. However, the functional heterogeneity and spatial ecological roles of CAFs in melanoma remain poorly characterized.</p> Methods <p>We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq data to systematically dissect CAF molecular programs in melanoma using weighted gene co-expression network analysis (WGCNA). Spatial distribution, CellChat, and ligand–receptor interaction analyses were applied to construct CAF-centered immune exclusion networks. A functional scoring model (riskScore) based on the CAF-M1 module was developed to evaluate clinical relevance.</p> Results <p>CAF was spatially co-localized with endothelial cells, and engaged in strong crosstalk with multiple immune cell types via pathways such as COLLAGEN–integrin and THBS1–CD47. The derived riskScore model demonstrated robust prognostic value across TCGA-SKCM cohort.</p> Conclusion <p>Through spatial aggregation and multifaceted immune signaling, CAF constructs a multilayered immune-exclusion network in melanoma, linking stromal remodeling to immune evasion. These findings offer novel insights into CAF-driven immune resistance and may inform future stratified immunotherapeutic strategies.</p>

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Exploration of the roles of CAFs in melanoma based on single-cell transcriptomics and spatial transcriptomics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Sheng Hong,
  • Yuhan Zhao,
  • Anni Hu,
  • Yizhong Zhang,
  • Yuming Li,
  • Yan Rong,
  • Zukai Li,
  • Wenzhuo Su,
  • Lude Zhu

摘要

Background

Cancer-associated fibroblasts (CAFs) are increasingly recognized as critical contributors to the limited efficacy of immunotherapy, particularly through the establishment of immune-excluded tumor microenvironments. However, the functional heterogeneity and spatial ecological roles of CAFs in melanoma remain poorly characterized.

Methods

We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq data to systematically dissect CAF molecular programs in melanoma using weighted gene co-expression network analysis (WGCNA). Spatial distribution, CellChat, and ligand–receptor interaction analyses were applied to construct CAF-centered immune exclusion networks. A functional scoring model (riskScore) based on the CAF-M1 module was developed to evaluate clinical relevance.

Results

CAF was spatially co-localized with endothelial cells, and engaged in strong crosstalk with multiple immune cell types via pathways such as COLLAGEN–integrin and THBS1–CD47. The derived riskScore model demonstrated robust prognostic value across TCGA-SKCM cohort.

Conclusion

Through spatial aggregation and multifaceted immune signaling, CAF constructs a multilayered immune-exclusion network in melanoma, linking stromal remodeling to immune evasion. These findings offer novel insights into CAF-driven immune resistance and may inform future stratified immunotherapeutic strategies.