Cancer-associated fibroblasts in triple-negative breast cancer: heterogeneity, tumor-stroma crosstalk, and therapeutic resistance

Abstract

Triple-negative breast cancer (TNBC) comprises a clinically and biologically heterogeneous group of breast cancers defined by the absence of estrogen receptor and progesterone receptor expression and the lack of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. Although systemic treatment has expanded beyond chemotherapy to include immune checkpoint blockade, poly(ADP-ribose) polymerase (PARP) inhibition in selected patients with germline BRCA1/2 variants, and antibody-drug conjugates in advanced disease, therapeutic resistance and disease recurrence remain major challenges. Cancer-associated fibroblasts (CAFs) are abundant stromal cells that contribute to the organization and function of the TNBC microenvironment. Rather than representing a single uniformly tumor-promoting population, CAFs encompass transcriptionally and functionally diverse states that vary across tumors, spatial niches, and treatment contexts. Current evidence supports roles for selected CAF populations in extracellular matrix (ECM) remodeling, paracrine signaling, metabolic exchange, immune-cell positioning, and adaptation to therapeutic stress. Recent single-cell and spatial studies have further identified ECM-rich, inflammatory, hypoxia-associated, and progenitor-like fibroblast states that correlate with distinct immune landscapes and treatment responses. However, many proposed CAF markers are shared across states, nomenclature remains inconsistent among datasets, and most CAF-directed therapeutic strategies are supported primarily by preclinical evidence. This review summarizes the current understanding of CAF heterogeneity in TNBC, examines the mechanisms through which fibroblast states influence tumor progression and antitumor immunity, and critically evaluates their contribution to chemotherapy and immunotherapy resistance. Particular attention is given to the distinction between mechanistic evidence and associative transcriptomic findings, as well as to the translational challenges that must be addressed before CAF-based biomarkers or therapies can be incorporated into routine TNBC management.