In addition to cancer cells, solid tumors contain a complex network of non-malignant cells and extracellular matrix (ECM) components that collectively shape tumor survival, growth, metastasis, and therapeutic response. CAFs are among the most abundant stromal cell types within solid tumors and contribute to ECM remodeling, immune regulation, and treatment resistance1-3. By shaping the TME, CAFs can influence the effectiveness of tumor-directed therapies and represent a therapeutic target themselves.
How CAFs Influence Therapeutic Strategies
One of the greatest challenges in treating solid tumors is overcoming the protective environment surrounding cancer cells. In highly fibrotic tumors, CAFs contribute to the formation of dense, scar-like extracellular matrix structures known as desmoplasia. This remodeled tumor stroma can create a physical barrier that limits therapeutic penetration and immune cell infiltration. Additionally, CAFs secrete factors like TGF-β and IL-6 that inhibit T-cell and natural killer cell activity and promote a protective microenvironment that actively suppresses anti-tumor immunity2.
High CAF abundance within the tumor stroma has been associated with poor clinical outcomes across multiple solid tumor types. Pancreatic ductal adenocarcinoma (PDAC) is one of the most striking examples, where CAF-rich stroma has been reported to comprise up to 70–90% of tumor tissue volume, contributing to tumor resistance to chemotherapy and immunotherapy4.
These observations have driven growing interest in tumor cell-extrinsic therapeutic strategies, such as CAF-directed therapies, rather than cancer cells themselves. By modifying the stromal environment, these approaches aim to improve therapeutic access, enhance immune activity, and increase the effectiveness of combination therapies.
Current CAF-targeted strategies generally fall into three categories1:
- Depleting CAFs: Directly or indirectly reducing tumor-promoting CAF populations
- Modulating CAF function: Limiting the tumor-promoting and immunosuppressive activities of CAFs
- Reprogramming CAFs: Shifting activated CAFs toward a more quiescent or normalized state to restore a less tumor-supportive microenvironment.
As researchers seek to better understand how CAFs influence therapeutic response and explore strategies to target the tumor microenvironment, experimental models are needed that can more accurately recapitulate the dynamic cellular interactions and biological complexity of the TME5.
Rebuilding the TME In Vitro
Traditional tumor models that focus on cancer cells alone often fail to capture how stromal components such as CAFs influence therapeutic response. New approach methodologies (NAMs), including advanced patient-derived 3D co-culture systems, help address this limitation by recreating key features of the TME in vitro. Building these models begins with access to the appropriate patient-derived analytes.
CAFs can be isolated from DTCs by exploiting their adherent growth characteristics. When primary DTCs are seeded onto collagen-coated culture plates, CAFs adhere and expand, enabling researchers to establish patient-derived CAF cultures for downstream functional studies6.
