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Exploration of the roles of CAFs in melanoma based on single-cell transcriptomics and spatial transcriptomics
Sheng Hong1, Yuhan Zhao2, Anni Hu3
1Department of Dermatology, First Affiliated Hospital of Naval Military Medical University, Shanghai, China.
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.
Insights
Cancer-associated fibroblasts (CAFs) create immune-excluded environments in melanoma, hindering immunotherapy. Understanding CAF spatial roles and signaling is key to overcoming immune resistance and improving cancer treatment strategies.
Area of Science:
- Oncology
- Immunology
- Bioinformatics
Background:
- Cancer-associated fibroblasts (CAFs) are implicated in immunotherapy resistance by promoting immune exclusion.
- The functional diversity and spatial roles of CAFs in melanoma are not well understood.
Purpose of the Study:
- To systematically analyze CAF molecular programs and spatial ecology in melanoma.
- To construct CAF-centered networks driving immune exclusion.
- To develop a clinical prognostic model based on CAF activity.
Main Methods:
- Integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq data.
- Employed weighted gene co-expression network analysis (WGCNA) for CAF molecular profiling.
- Utilized spatial distribution, CellChat, and ligand-receptor analyses to map immune exclusion networks.
Main Results:
- CAFs were spatially co-localized with endothelial cells and interacted with immune cells via specific pathways (e.g., COLLAGEN-integrin, THBS1-CD47).
- A CAF-M1 module-based risk score demonstrated significant prognostic value in the TCGA-SKCM cohort.
Conclusions:
- CAFs establish a complex immune-exclusion network in melanoma through spatial aggregation and signaling, linking stromal remodeling to immune evasion.
- These findings provide insights into CAF-mediated immune resistance and potential targets for stratified immunotherapy.
Related Concept Videos
02:21Cancers Originate from Somatic Mutations in a Single Cell
02:17The Tumor Microenvironment
01:09Introduction to Fibroblasts