D Renovaldi, YH Huang.
International PhD Program in Medicine, Taipei Medical University

Abstract
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) and play critical roles in tumor progression, immune evasion, and therapy resistance. Their interaction with tumor cells and other stromal components reshapes the TME, supporting tumor growth and contributing to treatment failure. This review examines the biological functions of CAFs in solid tumors, focusing on their contributions to tumor progression, and provides an overview of current and emerging therapeutic strategies targeting CAFs. Emphasis is placed on the use of cell and gene therapies in modifying CAF function, including their depletion, reprogramming, and modulation within the ECM to reduce metastasis. The review also discusses ongoing clinical trials targeting the TME and CAFs.

Keywords: Cancer-associated fibroblasts, tumor microenvironment, tumor progression, CAF-targeted therapies, extracellular matrix, immune modulation, clinical trials.

1.Introduction

Tumor progression is driven not only by the genetic alterations of cancer cells but also by their interactions with the surrounding tumor microenvironment (TME). The TME comprises various cellular and non-cellular components, including cancer cells, immune cells, blood vessels, extracellular matrix (ECM), and stromal cells, with cancer-associated fibroblasts (CAFs) being one of the most influential types of stromal cells. CAFs are implicated in various processes, including the remodeling of the ECM, secreting cytokines and growth factors, and interacting with other TME cells. Understanding the diverse roles of CAFs and the molecular mechanisms governing their function is essential for developing targeted therapies that could disrupt their tumor-promoting activities and improve the clinical management of cancer (1) (2).

2.Cancer-Associated Fibroblasts: Origin and Characteristics

2.1 Origins and Heterogeneity of CAFs

CAFs originate from various precursor cell types, including tissue-resident fibroblasts, mesenchymal stem cells (MSCs), endothelial cells through endothelial-mesenchymal transition (EndMT), and epithelial cells via epithelial-mesenchymal transition (EMT) (2) (3). Their origin is tissue-dependent and varies across different types of cancer. CAFs are highly heterogeneous, with distinct subpopulations exhibiting varying phenotypic and functional characteristics. Common markers for CAFs include fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA), and fibroblast-specific protein-1 (FSP-1), but these markers are not exclusive to CAFs, complicating their identification and functional characterization (3).

The heterogeneity of CAFs arises not only from their diverse origins but also from the dynamic nature of their activation and the signals they receive from the tumor cells and surrounding TME. This diversity allows CAFs to adapt to different tumor stages and environmental conditions, contributing to their multifaceted roles in cancer progression (1).

2.2 Biological Functions of CAFs in Tumor Progression

CAFs play several important roles in promoting tumor progression. One of their key functions is the remodeling of the ECM. Through the secretion of ECM proteins like collagen and fibronectin, CAFs create a supportive scaffold for tumor cells and facilitate cell adhesion, migration, and invasion (3). The altered ECM structure, often denser and stiffer than in normal tissues, can promote tumor cell survival and proliferation, and also hinder immune cell infiltration (2).

CAFs also secrete a variety of growth factors, cytokines, and chemokines, such as TGF-β, VEGF, IL-6, and CXCL12, which modulate tumor cell behavior and the immune response. These secreted factors can support tumor cell growth, induce angiogenesis, and create an immunosuppressive TME, thereby allowing tumors to evade immune surveillance and resist therapy (3).

Furthermore, CAFs interact with immune cells to promote immune evasion. By secreting factors like TGF-β and IL-6, CAFs recruit immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), into the TME, which inhibit the function of tumor-infiltrating lymphocytes (TILs) and prevent effective immune responses (1) (3).

3. Mechanisms of CAF-Mediated Tumor Progression

3.1 CAF mediactes  ECM Remodeling and Tumor Growth

CAFs are major contributors to the dynamic remodeling of the ECM, which is a crucial process for tumor progression. The ECM not only provides structural support to the tumor but also acts as a regulatory component of cellular behavior. CAFs secrete matrix metalloproteinases (MMPs), which degrade the ECM, facilitating tumor cell migration and invasion(2). CAFs also influence the mechanical properties of the ECM, making it stiffer and more resistant to normal tissue architecture, which can further support the growth and spread of tumor cells (3).

In addition to ECM degradation, CAFs also secrete various cytokines and growth factors that promote the survival and proliferation of tumor cells. These factors, such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), activate signaling pathways that enhance tumor cell survival and motility (3).

3.2 CAF regulates Immune Modulation

CAFs play a pivotal role in shaping the immune landscape of the TME. By secreting immunosuppressive cytokines such as TGF-β and IL-6, CAFs create an environment that favors immune evasion. These cytokines recruit immunosuppressive cells, such as Tregs and MDSCs, which inhibit the activity of tumor-infiltrating lymphocytes (TILs) (3). This immunosuppressive niche not only allows tumors to escape immune surveillance but also contributes to resistance against immunotherapies.

In addition to their direct effects on immune cells, CAFs also contribute to the creation of a “physical barrier” by remodeling the ECM, which hinders the infiltration of immune cells into the tumor tissue (2). The dense ECM produced by CAFs can physically restrict immune cell movement and prevent them from effectively targeting tumor cells.

3.3 CAFInduces Angiogenesis

CAFs are also involved in promoting angiogenesis, the process by which new blood vessels are formed to supply nutrients and oxygen to growing tumors. CAFs secrete pro-angiogenic factors, such as VEGF and PDGF, which stimulate the growth of blood vessels and enhance tumor vascularization (1). This increased blood supply not only supports tumor growth but also facilitates the dissemination of tumor cells to other parts of the body. Additionally, CAFs can alter the properties of blood vessels, making them more permeable and promoting the infiltration of immune cells and other stromal cells (3).

4. Targeting CAFs in Cancer Therapeutics

4.1 CAF Depletion

Depleting CAFs is one of the most direct approaches to disrupt their pro-tumorigenic functions. This can be achieved through various strategies, such as the use of chimeric antigen receptor (CAR)-T cells targeting FAP-expressing CAFs (2). The depletion of CAFs has been shown to reduce tumor growth and increase the effectiveness of immune therapies by alleviating immune suppression in the TME (3).

Additionally, nanoparticle-based drug delivery systems (NDDS) are being developed to target CAFs. These systems can passively target CAFs based on the altered properties of the TME, such as increased permeability in the tumor vasculature(3). By delivering drugs directly to CAFs, NDDS can promote CAF depletion and reduce their ability to support tumor progression.

4.2 CAF Reprogramming and  Normalization

Another strategy involves reprogramming CAFs from a pro-tumorigenic to a tumor-suppressive phenotype. This can be achieved through the use of small molecules or gene therapy approaches that block the activation of CAFs or induce their conversion into quiescent fibroblasts (2). For example, inhibiting TGF-β signaling in CAFs has been shown to reduce their tumor-promoting activities and improve the TME (3).

The normalization of CAFs can also be achieved by targeting the pathways that regulate ECM remodeling and immune modulation. By reversing the activated state of CAFs, it is possible to restore a more favorable TME that supports effective immune responses and reduces tumor growth (3).

4.3 CAF Modulation on  Tumor Cells and ECM

Nanomedicines are being developed to modulate the effects of CAFs on both tumor cells and the ECM. These therapies aim to inhibit the secretion of cytokines and growth factors by CAFs, thereby reducing tumor cell survival and invasion(3). For example, nanoparticles loaded with drugs that target CAF-derived ECM components can reduce tumor stiffness and improve drug delivery (2).

Additionally, therapies aimed at modulating the physical properties of the ECM, such as reducing its rigidity, can enhance the infiltration of immune cells and improve the efficacy of chemotherapy and immunotherapy (1).

5. Clinical Trials Targeting CAFs and Tumor Microenvironment 

Several clinical trials are underway to explore therapies targeting the CAFs and TME, focusing on CAF depletion, reprogramming, and ECM remodeling.

FAP-Targeted CAR-T Cells

Chimeric antigen receptor (CAR)-T cells targeting fibroblast activation protein (FAP) expressed by CAFs have been tested in preclinical studies and are currently being evaluated in clinical trials. One such trial, NCT03099159, focuses on using CAR-T cells to target FAP+ CAFs in solid tumors. The aim is to reduce the supportive stromal elements that enable tumor growth and metastasis.

Losartan for ECM Remodeling

Losartan, a drug that inhibits collagen production by CAFs, has been evaluated in clinical trials as an adjunct to chemotherapy. A phase II trial, NCT01821729, investigated the combination of losartan with chemotherapy in patients with pancreatic cancer to reduce ECM stiffness and improve drug delivery (1).

Anti-FAP Antibodies

A clinical trial (NCT02314296) is testing the use of FAP-targeted monoclonal antibodies in combination with chemotherapy for patients with advanced solid tumors. The goal is to selectively target CAFs and reduce tumor-supporting ECM production, ultimately improving therapeutic outcomes (2).

TGF-β Inhibition

TGF-β is a key regulator of CAF activation and ECM remodeling. Clinical trials targeting TGF-β signaling, such as NCT02925304, aim to inhibit CAF activation in various cancers, to reverse the pro-tumorigenic effects of CAFs, and enhance the effectiveness of other cancer therapies (3).

These trials are promising, but challenges remain in selectively targeting CAFs without affecting normal tissue function. Ongoing research into the heterogeneity of CAFs and better targeting strategies is crucial for improving the clinical success of these therapies (2) (3).

6. Challenges and Future Directions

Despite the promising potential of CAF-targeted therapies, several challenges remain. The heterogeneity of CAFs, with their dual roles as both tumor-promoting and tumor-suppressive cells, complicates the development of universal therapies(2). Furthermore, the dense and abnormal vasculature in the TME presents barriers to effective drug delivery, necessitating the development of advanced delivery systems like nanoparticles (3).

Future research should focus on identifying biomarkers that distinguish between tumor-promoting and tumor-suppressive CAFs and developing strategies to target specific CAF subpopulations. Additionally, combining CAF-targeted therapies with conventional treatments like chemotherapy and immunotherapy may provide more effective cancer treatments (3).

7. Conclusion

CAFs are central to the progression of solid tumors, influencing tumor growth, immune evasion, and treatment resistance. Targeting CAFs through depletion, reprogramming, and modulation represents a promising therapeutic approach to alter the TME and improve cancer treatment outcomes. However, the complexity of CAF biology and the challenges posed by the TME require continued research and innovation to optimize these therapies and achieve better clinical results.

References

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