What question did this study set out to answer?

This research aims to characterize the diverse roles of cancer-associated fibroblasts (CAFs) in breast cancer subtypes, focusing on immune suppression and treatment outcomes.

June 27, 2026Open Access

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

Key Points

This research aims to characterize the diverse roles of cancer-associated fibroblasts (CAFs) in breast cancer subtypes, focusing on immune suppression and treatment outcomes.
Integrated three single-cell RNA sequencing datasets from 29 breast cancer patients.
Analyzed bulk RNA-seq data from The Cancer Genome Atlas (TCGA) to examine CAF subsets and immune interactions.
Identified a novel CAF subset, msCAF, through gene signature analysis related to immune suppression and chemotherapy response.
Identified four stromal populations, including a novel CAF subset, msCAF, associated with immune suppression.
msCAF abundance inversely correlated with T-cell function, particularly in triple negative breast cancer (TNBC) environments.
msCAF gene signatures predicted chemotherapy response, with distinct prognostic relevance for Luminal A and TNBC tumors.

Abstract

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. 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. 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. 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.

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