The role of CAFs in therapeutic resistance in triple negative breast cancer: an emerging challenge

Abstract

The tumor microenvironment (TME) is a crucial element of cancerous tissue and has emerged as a promising target for therapeutic strategies. The complex variety of stromal cells within the TME plays a vital role in determining the tumor's aggressiveness and its resistance to treatment. Tumor progression is not solely driven by cancer cells harboring genetic mutations but is also significantly influenced by non-cancerous host cells within the TME, which strongly impact tumor growth, metastasis, and the response to therapies. Cancer-associated fibroblasts (CAFs) are a diverse group of stromal cells within the TME. They play dual roles, both promoting and inhibiting tumor growth, making them intriguing targets for enhancing cancer therapies. Their significant contribution to creating a tumor-supportive environment has diminished the effectiveness of various cancer treatments, including radiation, chemotherapy, immunotherapy, and hormone therapy. Research has increasingly focused on understanding how CAFs contribute to therapy resistance in triple-negative breast cancer (TNBC) to improve treatment outcomes. However, the ways in which CAF patterns affect the TME and the response to immunotherapy in TNBC are not yet well understood and the interactions between CAFs, tumor cells, and immune cells in TNBC remain largely unexplored. In this review, we thoroughly exam ine the relationship between TNBC progression and CAF patterns. We discuss the current understanding of CAF heterogeneity, their role in tumor progression, and their impact on the tumor's response to therapeutic agents in TNBC. Additionally, we explore the potential and possible strategies for therapies targeting CAFs.

Keywords: CAF; TME; TNBC; cancer therapies; therapeutic resistance.

FIGURE 1

Composition of the tumour microenvironment. The tumor microenvironment (TME) consists of a variety of cell types and secreted factors that serve as potential targets for anticancer therapies. It includes heterogeneous cancer cells, immune cells such as T and B lymphocytes, tumor-associated macrophages (TAMs), dendritic cells (DCs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and eosinophils. Additionally, stromal cells like cancer-associated fibroblasts (CAFs), pericytes, and mesenchymal stromal cells, along with blood and lymphatic vascular networks, as well as tissue-specific cells such as neurons and adipocytes, are also present. These cells release extracellular matrix (ECM) components, growth factors, cytokines, and extracellular vesicles (EVs), which play a crucial role in cell communication within the TME and beyond. Since each cell type uniquely influences tumor progression and therapeutic response, multiple TME-targeted therapies have been developed. The most advanced approaches, either approved or in clinical trials, primarily focus on TAMs, DCs, T cells, tumor vasculature, ECM, and CAFs.

FIGURE 2

Cellular origin of CAF. CAFs can originate from various cell typoe such as stellate cells, endothelial cells, adiphocyte,MSCs, pericytes, epithelial cells as well as normal fibroblast. CAF, cancer associated fibroblast. EMT, epitheliual mesenchimal transition, EndMT, endothelial to mesenchimal transition; MSC, mesenchimal stem cells.

FIGURE 3

(CAFs) contribute to collagen production in breast cancer, presenting new therapeutic opportunities. Fibroblasts derived from adipocytes near breast tumor cells enhance the secretion of fibronectin and collagen I, facilitating tumor cell migration and invasion, often through activation of the Wnt/β-catenin pathway. Endo180 supports cell migration and extracellular matrix (ECM) remodeling by mediating collagen uptake. Additionally, PYCR1, a crucial enzyme in proline synthesis, plays a role in ECM production, promoting tumorigenesis and emerging as a potential therapeutic target.