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Background <p>The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are key regulators of these processes, yet their subtype-specific contributions in BC remain insufficiently defined.</p> Methods <p>We integrated three single-cell RNA sequencing datasets from 29 BC patients to characterize stromal populations. Bulk RNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between CAF subsets and immune infiltration. Gene signatures were derived to identify subtype-specific CAF–immune interactions, prognostic markers, and potential predictors of chemotherapy response.</p> Results <p>Three conserved stromal populations (iCAFs, myCAFs, and pericytes) were identified, along with a previously unrecognized subset, the cluster 3 (CL3) CAF-like cells, referred as metabolic stressed CAF (msCAF). msCAF cells displayed transcriptional programs associated with antigen presentation, stress response, glycolysis, and extracellular matrix remodeling. Their abundance was inversely correlated with T-cell infiltration and function, in a subtype-specific manner: triple negative breast cancer (TNBC) was enriched for msCAFs in immune-infiltrated but functionally constrained microenvironments, whereas Luminal A tumors exhibited weaker immune infiltration with heterogeneous CAF–immune associations. msCAFs were characterized by a conserved gene signature (<i>HLA-A</i>, <i>HLA-C</i>, <i>IL32</i>, <i>EMP3</i>) and subtype-specific genes related to T-cell exhaustion. Several genes demonstrated prognostic relevance with distinct patterns in Luminal A (<i>IER3</i>, <i>TIMP1</i>, <i>TBX3</i>, <i>SEC61G</i>) and TNBC (<i>ADM</i>, <i>C4orf3</i>, <i>LDHA</i>) tumors, as well as shared biomarkers (<i>FN1</i>, <i>LOXL2</i>, <i>P4HA1</i>). Multiple msCAF genes also predicted chemotherapy response, suggesting utility as treatment stratification biomarkers.</p> Conclusion <p>msCAFs represent a clinically relevant CAF subset that drives immune suppression, impacts subtype-specific prognosis, and influences therapy response in BC. These findings highlight msCAFs as promising targets for enhancing immunotherapy and personalizing treatment strategies.</p>

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Single-cell profiling reveals a novel CAF subpopulation linking stromal heterogeneity to immune suppression in breast cancer subtypes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Virginia Vigiano Benedetti,
  • Federica Conte,
  • Daniele Santoni,
  • Tancredi Massimo Pentimalli,
  • Roberto Bei,
  • Loredana Cifaldi,
  • Giovanni Barillari,
  • Francesco Spallotta,
  • Chiara Cencioni,
  • Ombretta Melaiu

摘要

Background

The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are key regulators of these processes, yet their subtype-specific contributions in BC remain insufficiently defined.

Methods

We integrated three single-cell RNA sequencing datasets from 29 BC patients to characterize stromal populations. Bulk RNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between CAF subsets and immune infiltration. Gene signatures were derived to identify subtype-specific CAF–immune interactions, prognostic markers, and potential predictors of chemotherapy response.

Results

Three conserved stromal populations (iCAFs, myCAFs, and pericytes) were identified, along with a previously unrecognized subset, the cluster 3 (CL3) CAF-like cells, referred as metabolic stressed CAF (msCAF). msCAF cells displayed transcriptional programs associated with antigen presentation, stress response, glycolysis, and extracellular matrix remodeling. Their abundance was inversely correlated with T-cell infiltration and function, in a subtype-specific manner: triple negative breast cancer (TNBC) was enriched for msCAFs in immune-infiltrated but functionally constrained microenvironments, whereas Luminal A tumors exhibited weaker immune infiltration with heterogeneous CAF–immune associations. msCAFs were characterized by a conserved gene signature (HLA-A, HLA-C, IL32, EMP3) and subtype-specific genes related to T-cell exhaustion. Several genes demonstrated prognostic relevance with distinct patterns in Luminal A (IER3, TIMP1, TBX3, SEC61G) and TNBC (ADM, C4orf3, LDHA) tumors, as well as shared biomarkers (FN1, LOXL2, P4HA1). Multiple msCAF genes also predicted chemotherapy response, suggesting utility as treatment stratification biomarkers.

Conclusion

msCAFs represent a clinically relevant CAF subset that drives immune suppression, impacts subtype-specific prognosis, and influences therapy response in BC. These findings highlight msCAFs as promising targets for enhancing immunotherapy and personalizing treatment strategies.