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Review

Drug Delivery System Targeting Cancer-Associated Fibroblast for Improving Immunotherapy

       

Authors Zhang Z, Wang R, Chen L 

Received 12 October 2024

Accepted for publication 16 December 2024

Published 11 January 2025 Volume 2025:20 Pages 483—503

DOI https://doi.org/10.2147/IJN.S500591

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. RDK Misra

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Zhongsong Zhang,1 Rong Wang,1 Long Chen2

1School of Clinical Medicine, Chengdu Medical College, Chengdu, 610550, People’s Republic of China; 2School of Basic Medical Sciences, Chengdu Medical College, Chengdu, 610550, People’s Republic of China

Correspondence: Long Chen, Email [email protected]

Abstract: Cancer-associated fibroblasts (CAFs) are a heterogeneous population of non-malignant cells that play a crucial role in the tumor microenvironment, increasingly recognized as key contributors to cancer progression, metastasis, and treatment resistance. So, targeting CAFs has always been considered an important part of cancer immunotherapy. However, targeting CAFs to improve the efficacy of tumor therapy is currently a major challenge. Nanomaterials show their unique advantages in the whole process. At present, nanomaterials have achieved significant accomplishments in medical applications, particularly in the field of cancer-targeted therapy, showing enormous potential. It has been confirmed that nanomaterials can not only directly target CAFs, but also interact with the tumor microenvironment (TME) and immune cells to affect tumorigenesis. As for the cancer treatment, nanomaterials could enhance the therapeutic effect in many ways. Therefore, in this review, we first summarized the current understanding of the complex interactions between CAFs and TME, immune cells, and tumor cells. Next, we discussed common nanomaterials in modern medicine and their respective impacts on the TME, CAFs, and interactions with tumors. Finally, we focus on the application of nano drug delivery system targeting CAFs in cancer therapy.

Keywords: cancer-associated fibroblasts, drug delivery, nanomedicine, tumor microenvironment, cancer immunotherapy

Introduction

Nowadays, cancer remains one of the leading causes of death globally, accounting for more than 10 million deaths each year. CAFs has garnered increasing attention as therapeutic targets due to their indispensable role in tumor progression and their unique ability to remodel the tumor.1 Unlike other stromal or immune cells, CAFs are abundant and dynamically interact with both cancer cells and the surrounding TME, playing a pivotal role in tumor survival, proliferation, and metastasis.2,3 CAFs influence tumor biology through several distinct mechanisms, including remodeling the extracellular matrix (ECM), promoting angiogenesis, secreting growth factors and cytokines, and inducing immune evasion.4,5 These multifaceted functions make CAFs indispensable for sustaining tumor dynamics and an ideal target for therapeutic intervention compared to other cell types within the TME. More and more research have confirmed the relationship between CAFs and different cancers, finding that CAFs play a key role in all aspects of tumor,6 such as promoting tumor growth and spread, improving drug resistance, remodeling TME and immunosuppression. One prominent mechanism involves the transfer of exosomes directly to cancer cells. For example, CAFs exert their roles by directly transferring exosomes to colorectal cancer (CRC) cells, leading to a significant increase of miR-92a-3p levels in CRC cells, which causes metastasis and chemotherapy resistance in CRC patients.7 Additionally, there are different subtypes and phenotypes of CAFs in different tumors, which increases the difficulty of unified targeting of CAFs to treat cancer. However, it also adds the opportunities for specific targeted therapies about different cancers at the same time.8

With the development of targeted drug therapy, the advantages of nanomaterials have been continuously explored. Different nanomaterials possess unique physicochemical properties that offer significant advantages for improving drug delivery and treatment outcomes, medical nanomaterials can be broadly categorized into organic and inorganic types.9–11 These materials can be precisely engineered to target CAFs, thereby modifying the TME to bolster antitumor immunity. Targeting CAFs with nanomaterials disrupts the fibrotic stroma, reduces extracellular matrix (ECM) deposition, and mitigates the immunosuppressive milieu.12 Moreover, this disruption facilitates enhanced penetration of immune cells and therapeutic agents into the tumor core.13 Furthermore, nanomaterials can be designed to carry and release immunomodulators, thereby boosting the activation and proliferation of immune cells within the TME.13 Nanoparticles can be designed to target specific components of the immune system or TME, thereby enhancing the specificity and efficacy of immunotherapeutic agents.14 For instance, nanoparticles targeting CAFs can help dismantle the immunosuppressive stroma, thereby improving the infiltration and activity of cytotoxic T lymphocytes.15 In a word, nanomedicine represents the forefront of cancer therapy and offers targeted delivery systems that could reduce systemic toxicity and improve therapeutic indices.16

In conclusion, nanomedicine targeting CAFs integrates significant potential for advancing cancer immunotherapy. These systems utilize the unique properties of nanomaterials to precisely regulate the TME, enhancing both local and systemic immune responses. This enhancement improves anti-tumor immune responses and treatment outcomes, potentially improving survival rates and the quality of life for cancer patients.

Biological Characteristics of CAFs

Heterogeneity and Diversity in the Origin of CAFs

CAFs originate from diverse sources, with cells being the most common. For instance, normal fibroblasts may be recruited by tumor cells to tumor tissue and then converted into CAFs.17 Furthermore, CAFs result not only from the transformation of endothelial, epithelial, mesenchymal stem cells, adipocytes and other cells, but also from the differentiation of tumor stem cells.18–20 Additionally, some studies indicate that the sources of CAFs can also be influenced by physiological status, tumor type, environmental factors, and other variables.21 For example, in breast cancer, we find that adipocytes can be dedifferentiated into CAFs.22 Notably, some studies have proven that the lack of certain substances in a specific environment can also cause the differentiation of CAFs.23 For example, in Jerome Thiery’s article, he pointed out that vitamin A or D deficiency can also promote CAF differentiation in some cases.24 However, further evidence and research are required to investigate the origins of CAFs across various environments. Moreover, different subtypes of CAFs exhibit distinct biological characteristics and functions,25,26 such as invasive CAFs, immunosuppressive CAFs, stromal CAFs, and degenerative CAFs. Invasive CAFs are mainly involved in tumor invasion and metastasis, immunosuppressive CAFs help tumor cells evade immune surveillance, stromal CAFs are primarily responsible for constructing the tumor microenvironment, while degenerative CAFs are mainly involved in the formation of tumor drug resistance. Furthermore, CAFs in the studied tumor types, we can roughly divide CAFs into three categories (Figure 1), namely myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs).27–29 Interestingly, some studies suggest that balancing the proportions of CAF subgroups could be a significant clinical strategy,29 therefore, we could potentially provide specific treatments for patients based on different CAFs and their number in the future.30 In summary, distinct CAF subtypes are distributed across various tissues and organs.31 There are multiple subtypes of tumor-associated fibroblasts, each of which may play roles in different diseases and tissues.32 Understanding the characteristics and functions of these CAF subtypes is crucial for providing new ideas and directions for targeted therapy in the future,33 as it will help us deeply understand the tumor microenvironment and its regulatory mechanisms.

Figure 1 The Origin of CAFs. Fibroblast heterogeneity arises from diverse precursor cell origins, phenotypic variation, and distinct functions of each subset. Key cellular sources include local stellate cells, fibroblasts, and bone marrow-derived MSCs and macrophages. The main CAF subsets—myCAFs, iCAFs, and apCAFs—exhibit unique biological features, contributing to cancer progression’s phenotypic and functional diversity. These CAF subsets are dynamic and can interconvert through specific signaling pathways, such as TGFβ or IL-6, facilitating transitions between iCAFs and myCAFs. Reproduced from Yang D, Liu J, Qian H, Zhuang Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp Mol Med. 2023;55(7):1322–1332. http://creativecommons.org/licenses/by/4.0/.31.

Diversity of CAFs Markers

CAFs and their markers both play an important role in the development of tumors, especially, there are different biological functions of their markers in the TME. Therefore, understanding the functions and roles of these markers may be a vital part of comprehending cancer immunotherapy better. Up to now, it is widely acknowledged that the markers of CAFs have significant clinical application value.34 For example, these markers are invaluable for identifying and monitoring the presence and development of tumors. For simplicity, clinicians can diagnose tumors and evaluate their severity by detecting these markers in blood or tissue samples. Moreover, these markers can predict tumor responses to therapies and monitor treatment outcomes.35 So, we think these markers must have surprising clinical application prospects in the future.36

The discovery of markers is a long and hard process. In the 1970s, Gabbiani et al first identified α-smooth muscle actin (α-SMA) while studying granulation tissue during wound healing. Meanwhile, so far, α-SMA is still one of the classic markers of CAFs and is usually used to identify CAFs.37,38 However, recent studies have shown that CAFs of α-sma+ may have both pro- and anti-tumor properties.39,40 Furthermore, fibroblast activation protein (FAP) as a membrane protein is another classic marker,41 which was discovered by scientists in interstitial cells and certain types of cancer in the early 1990s. Platelet-derived growth factor receptor (PDGFR), which is highly expressed in CAFs and involved in the activation of CAFs and tumor promotion, was found in platelets and subsequent molecular cloning experiments, by Jan-Åke Gustafsson and Charles-Henri Heldin in 1978.42 With advancements and innovations in scientific detection methods, scientists have identified numerous different CAF markers through techniques like single-cell sequencing.43 Additional markers of CAFs include Vimentin, fibronectin (FN), laminin (LN), matrix metalloproteinases (MMPs), epithelial cell adhesion molecule (EPCAM), synovial glycoprotein (SGR), and mannose-binding lectin (MBL).44–47 Furthermore, more interestingly, in breast cancer-associated fibroblasts, we find that specific genes such as NOTCH3 and HES4 act as markers involved in CAF self-renewal and proliferation.48 This discovery may offer a novel approach to integrating gene technology with these markers. In general, although we have discovered many new markers, the biomarkers of fibroblasts we identified are still limited so far. For a more in-depth discussion, how do we distinguish between fibroblasts, CAFs, or different subtypes of CAFs by using simple markers is crucial, but it still remains a challenge.45 Hopefully, this challenge will be resolved in the near future.

Interactions Between CAFs and Tumor Cells

Studies have indicated that the quantity and activity levels of CAFs are closely associated with tumor prognosis in cancer patients. The impact of CAFs on tumor development and prognosis is multifaceted and influenced by various factors.49 However, during the development of cancer, CAFs interact with tumor cells by expressing extracellular signaling molecules such as osteopontin (OPN) and hepatocyte growth factor (HGF), thereby influencing tumor cell proliferation, invasion, and migration.50 Subsequently, in the TME, CAFs regulate tumor development by modulating metabolic activities, including glucose and pH balance adjustments,51 and by influencing mitochondrial function, thereby participating in tumor cell energy metabolism. Other research has shown that mechanical forces generated by CAFs can affect tumor cell movement and morphology by activating intracellular cytoskeletal systems and signaling pathways,52 which may speed the spread of tumors. Exosomes, small extracellular vesicles, mediate intercellular signaling and maintain tissue and organ stability through various mechanisms. Exosomes secreted by CAFs also play a crucial role in influencing tumors. For example, in the study by Piwocka et al, CAF-derived exosomes carrying microRNA-296-3p were found to promote malignant behaviors such as proliferation, migration, invasion, and drug resistance in ovarian cancer cells, this also suggests microRNA-296-3p as a potential diagnostic marker and therapeutic target.53 Then Zhang et al discovered that miR-522 enhances tumor cell resistance to chemotherapeutic drugs and inhibits ferroptosis in gastric cancer cells by targeting ALOX15 to suppress lipid peroxidation. Their research unveiled a novel intercellular pathway involving USP7, hnRNPA1, exo-miR-522, and ALOX15, which regulates lipid peroxidation levels in tumor cells, impacting their chemotherapy sensitivity.54

On the other hand, tumors or tumor cells can also influence CAFs. Activation pathways of CAFs include direct interaction with tumor cells and activation through the Notch signaling pathway. Additionally, matrix remodeling by CAFs amplifies their activation, creating a positive feedback loop.55 Interestingly, in some cases, tumor cells can induce the “reverse Warburg effect” in CAFs, enriching energy in CAFs and promoting glycolytic pathway activation.31 However, in pancreatic ductal adenocarcinoma (PDAC), cancer cells induce autophagy in CAFs, leading to the secretion of non-essential amino acids like alanine, which support cancer cell needs by promoting the tricarboxylic acid cycle and lipid biosynthesis.56

In conclusion, CAFs are inextricably linked with tumors and tumor cells, making CAFs are not only therapeutic targets but also integral components of cancer treatment strategies.55 Therefore, we think future treatment strategies should consider tailored approaches based on different tumor types and CAF subtypes, this is the only way to address the challenge of one-size-fits-all treatments being insufficient and provide personalized treatment.57

The Interaction Between CAFs and TME

The tumor microenvironment (TME) is a complex ecosystem comprising various cell types, extracellular matrix (ECM), blood vessels, and immune cells. While CAFs are crucial components of the tumor microenvironment, interacting with tumor cells and playing significant roles in tumorigenesis and development (Figure 2).58 Current research reveals that CAFs can influence tumor immune evasion by activating or inhibiting the immune system. They also promote angiogenesis, regulate inflammatory responses, remodel the ECM, and induce CAF differentiation, among other functions.59,60 These activities occur within the tumor microenvironment, emphasizing the importance of investigating CAF interactions within the TME. Additionally, CAFs and the TME interact reciprocally, for example, with CAFs regulating the TME by secreting growth factors, chemokines, and other molecules that promote tumor formation.61 These regulatory activities include remodeling extracellular matrix and metabolic reprogramming.62 Moreover, CAFs engage in transmembrane signaling with other TME cells through various pathways, influencing disease progression.63 For example, CAFs secrete chemokines such as PDGF, IL-6, and TNF-α, which attract and recruit other cells in the TME to the tumor site, thereby further promoting tumor growth and metastasis.64 Recently, some studies highlighted the critical roles of exosomes in the TME for cancer and inflammation.65 Exosomes facilitate communication between CAFs and tumor cells, contributing to tumor occurrence, development, and metastasis.66,67 For instance, research by Sun et al has demonstrated that exosomal ncRNAs from CAFs participate in CRC microenvironment formation and may be linked to resistance mechanisms in CRC patients undergoing radiotherapy.68 Furthermore, the biological characteristics and functions of CAFs are also influenced by the tumor microenvironment. For instance, in environments with elevated levels of hyaluronic acid (HA) or oxidative stress, CAFs may be stimulated to exhibit more active tumor promoting behavior.69 Despite significant progress, many uncertainties persist regarding CAF functions in different TMEs,70,71 and further breakthroughs are expected.

Figure 2 The Interaction between CAFs and TME. This figure highlights the role of CAFs in shaping the TME. CAFs interact with immune cells (eg, TAMs, TANs, NK cells) and remodel ECM, promoting tumor invasion, immune suppression, and immune checkpoint expression (eg, PD-L1, B7-H3). By recruiting immunosuppressive cells like Tregs and MDSCs and suppressing CTL activity, CAFs establish a pro-tumorigenic TME, underscoring their potential as therapeutic targets. Reproduced from Mao X, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20(1):131. http://creativecommons.org/licenses/by/4.0/.46.

The Interaction Between CAFs and Immune Cells

Immune cells are an important part of the TME, and they play complex dual roles. In most cases, CAFs play a positive role in tumor immune suppression, closely intertwined with immune responses and immune cells. Therefore, we delve into the interactions between CAFs and specific immune cells. Generally, CAFs can interact with T cells, helper T cells, natural killer cells, macrophages, and myeloid-derived suppressor cells (MDSCs).24,52,72,73 For instance, a recent study by Ying et al highlighted that CAFs can inhibit T cell activation through inhibitory receptors like programmed death ligand 1 (PD-L1), thereby evading immune surveillance and attack.74 Concurrently, Zeng et al found in vitro that macrophages expressing M2 phenotype-related genes can enhance resistance to chemotherapy in CAFs and breast cancer cells.75 Furthermore, CAFs can even regulate cancer cell proliferation and migration by secreting extracellular signaling molecules such as growth factors and chemokines, recruiting immune cells to participate in cancer development.76 However, some studies indicated that different CAF subtypes have been observed to modulate the distribution and activity of immune cells within the tumor microenvironment in varying ways.58 Additionally, in a recent study through spatial transcriptomics analysis, Chen et al discovered distinct distributions and interactions of different cell types within the lung cancer tumor microenvironment. For example, CAFs and malignant cells typically cluster together to form the tumor core, whereas immune cells are predominantly located at the tumor periphery. Furthermore, various immune cell types such as macrophages and dendritic cells exhibit unique distribution patterns and functional characteristics.77

CAFs as Potential Therapeutic Targets

CAFs are a key component of the TME and are widely involved in and drive tumor progression. Multiple studies have shown that CAFs can secrete various growth factors, cytokines, chemokines, and matrix remodeling molecules to significantly alter the characteristics of the tumor microenvironment,78–80 which promotes tumor cell proliferation, angiogenesis, and immune escape. Therefore, these complex biological interactions between CAFs and TME make CAFs an important target for cancer immunotherapy.81

CAFs can produce and secrete large amounts of ECM proteins, such as collagen and fibronectin,80,82 which not only provide structural support for tumors but also promote tumor cell migration and invasion.80 For instance, CAFs are known to activate the transforming growth factor-beta (TGF-β) pathway, which results in increased ECM deposition and fibrosis. This fibrosis creates a physical barrier that prevents immune cells from infiltrating the tumor and limits the delivery of therapeutic agents.80,83 By targeting CAFs or disrupting the TGF-β signaling pathway, it is possible to degrade the ECM and improve the penetration of immune cells and drugs into the tumor core.84,85 Moreover, CAFs contribute to the creation of an immunosuppressive TME by secreting cytokines such as IL-6 and CXCL12,82,83 which can inhibit cytotoxic T lymphocyte (CTL) activity in different ways, ultimately allowing tumor cells to evade immune surveillance.86 Up to now, the CXCL12/CXCR4 signaling axis between CAFs and immune cells has been widely identified as a key mediator of immune evasion.87,88 In this regard, by using this signaling axis of CXCR4 antagonists, Biasci et al have confirmed the infiltration and enhancement of CTL activity within the tumor, which enhances the anti-tumor immune response.89 Additionally, in the new research of Sunil Singh et al, they found that CAFs can activate c-Met receptors on tumor cells by secreting hepatocyte growth factor (HGF) in triple negative breast cancer, and then promote proliferation and resistance to tyrosine kinase inhibitors.90 Additionally, several related studies have also suggested that targeting the HGF/c-Met axis presents another potential strategy to overcome drug resistance mediated by CAFs.91,92 Another promising strategy is to reprogram CAFs instead of completely eliminating them.93,94 However, CAFs exhibit significant heterogeneity, with different subtypes displaying both pro tumorigenic and potential anti-tumor properties.94 So it may be an extremely challenging task to reprogram different types of CAFs and explore their potential therapeutic effects. But in recent studies, the use of nanoparticles to specifically target CAFs has demonstrated considerable promise in enhancing treatment efficacy.95,96 By combining new advances in nanomaterials, we can utilize precise drug delivery or specific pathways associated with CAFs to targets CAFs, which holds great significance for advancing cancer immunotherapy.

Nanomaterials and Tumor Targeted Therapy

Classification of Nanomaterials

In recent years, the rapid development of nanomaterials and their increasing application in medicine have made medical nanomaterials a perennial research hotspot (Figure 3). In this review, we explore some nanomaterials discovered by modern medicine, such as nanoparticles, biomimetic nanoparticles, inorganic nanomaterials, organic-inorganic hybrid nanomaterials, conventional nanomaterials, and their specific roles in biological systems (as summarized in the Table 1).

Figure 3 Classification and Mechanisms of Nanosystems. Nanosystems can be classified into inorganic and organic types, based on their matrix characteristics and the materials they are composed of. Inorganic nanosystems include silver nanoparticles (NPs), mesoporous silica NPs, magnetic NPs, ZnO NPs, cobalt NPs, selenium NPs, and cadmium NPs, which are designed for high stability and reactive properties. Organic nanosystems, such as polymeric NPs, polymeric micelles, liposomes, nanostructured lipid carriers, and solid lipid NPs, provide biocompatibility and versatility for drug delivery. Reproduced from Eleraky NE, Allam A, Hassan SB, Omar MM. Nanomedicine fight against antibacterial resistance: an overview of the recent pharmaceutical innovations. Pharmaceutics. 2020;12(2):142. http://creativecommons.org/licenses/by/4.0/).97

Table 1 Classification of Nanomaterials

So far, we have known that tumor cells are influenced by various factors, including TME and CAFs, while nanomaterials can play direct or indirect roles in disrupting tumor cell infiltration, invasion, and proliferation. For instance, a recent experiment demonstrated that gold-silver core-shell hybrid nanomaterials can significantly inhibit the migration of adenocarcinoma cells promoted by fibroblasts and reduce their proliferation, thereby curtailing metastatic spread.111 In another study, ZnO@CuS nanoparticles enhanced tumor cell sensitivity to photothermal therapy and suppressed cell migration by generating free radicals.112 Furthermore, combining monoclonal antibodies with nanomaterials enables precise targeted therapy, sparing normal tissues.113 Additionally, the strategy of combining multiple drugs with nanomaterials offers novel approaches to cancer treatment.113 At present, radiotherapy and chemotherapy remain the pivotal methods in cancer treatment, with nanomaterials substantially enhancing their efficacy.114 For example, that gold nanocages coupled with radioactive isotopes enhance radiotherapy effectiveness by forming radiolabeled markers.107 Furthermore, another study that nanoscale radiosensitizers improve tumor cell sensitivity to radiation, thereby boosting radiotherapy outcomes.115 Moreover, nanomedicines, which carry chemotherapeutic drugs, can specifically target specific tumor cell receptors to increase drug accumulation and enhance chemotherapy efficacy.116 Addressing tumor drug resistance is critical, and nanomaterials offer promising solutions. Certain nanoliposomes prolong drug circulation to increase bioavailability,100 while nanomicelles can bind to multidrug resistance-associated proteins, facilitating drug entry into tumor cells.117,118 In the experiment of Cheng et al, they elaborated that a kind of gold nanocage pH-sensitive conjugates releases anticancer drugs in response to acidic conditions, enhancing drug concentration in tumor tissues and radiotherapy efficacy.119 Notably, nanoparticles have been shown to traverse the blood-brain barrier in multiple studies, modifying the TME and enhancing drug efficacy.101,102 Therefore, nanomedicines may have great application potential in neurological diseases. Lastly, beyond therapeutic applications, some nanomaterials offer diagnostic functionalities, such as fluorescence and magnetic resonance imaging capabilities. For example, iron oxide nanomaterials enable the observation of tumor location and size through advanced magnetic resonance imaging techniques.44

In conclusion, nanomaterials will be increasingly important roles widely used in the field of Medicine. However, while exploring new materials, we should further provide their applications in the medical field.97 Especially in the immunotherapy of cancer, there are still many difficulties that need more time to solve.

Nanomaterials as Multifunctional Tools for Targeting and Modulating CAFs

From numerous previous studies, it has been demonstrated that nanomaterials have significant effects on CAFs.35 On one hand, some nanomaterials served as carriers for chemotherapeutic drugs or bioactive molecules, delivering them directly to CAFs, and thereby enhancing therapeutic efficacy while minimizing impact on healthy tissues. For instance, Li et al developed reversibly bonded nanoparticles capable of delivering anticancer drugs precisely to CAFs, illustrating their potential in targeted therapy.120 Additionally, in a review by Aljabali AA et al, they highlighted the impact of nanomaterials on the immune system, some nanomaterials have immunomodulatory properties, facilitating the clearance or control of CAFs by modulating immune responses.121 On the other hand, specific nanomaterials are often designed to target molecules on the surface of CAFs, such as FAP, to inhibit their activity.122 For example, Zhou et al developed α FAP-Z@FRT nanomaterials, which selectively target FAP expression in CAFs without affecting non-tumor tissues. Moreover, different nanomaterials can also affect CAFs in many aspects. For instance, Li et al utilized a complex nanocomposite, which involves graphene oxide, gold nanoparticles, and fluorescent dyes, then it is observed that this composite material can release chemicals to selectively eliminate CAFs upon near-infrared laser irradiation.120 Additionally, certain nanomaterials act as carriers for photothermal therapy, generating heat upon exposure to light to induce CAF apoptosis.35 For instance, Mukherjee et al demonstrated that 20 nm gold nanoparticles transform CAFs into a quiescent state rich in lipids, to inhibit matrix deposition. Similarly, many studies point out gold nanocages, nanoparticles, and nanorods can all target and suppress CAF growth and function through photothermal effects.98,123 To be more specific, gold nanocages disrupt CAF structures via photothermal therapy, thereby impeding their proliferation and secretory functions.123 And gold nanoparticles specifically target CAFs to inhibit their proliferation and migration capabilities.98 More interestingly, so far, recent studies have reported paradoxical effects of certain nanomaterials on CAFs, stimulating their proliferation and migration.93,119 So, these interesting studies may provide a new reverse thinking for targeted therapies of CAFs and cancer immunotherapy. Moreover, we discovered certain nanomaterials enable the detection of gene expression and products in CAFs, which may facilitate studies on their role in tumor development in the future.116 Although these new ideals currently lack practical applications, these advancements hold significant promise for future research and clinical implementation.

Nanomaterials and Their Interactions with CAFs in the TME

Research on how nanomaterials interact with CAFs within the TME is a key area in modern cancer therapy.124 Nanomaterials modulate cellular-level biological activities within the TME, due to their unique size and surface properties.125 These materials influence the behavior of CAFs either through direct physical interactions or by releasing specific chemical signals, thereby promoting or inhibiting their pro-tumorigenic functions. For instance, some nanomaterials alter the ETM composition, impacting the support CAFs offer to tumor cell.16 Nanomaterials in the tumor microenvironment not only serve as carriers for drugs and bioactive molecules,126 but also enhance treatment efficacy while minimizing effects on healthy tissues.120 For instance, specific nanomaterials regulate the availability of oxygen and nutrients, promoting tumor cell apoptosis and reducing tumor volume.107,127,128 Additionally, these nanomaterials can modulate the immune system, targeting and activating various immune cells to bolster the immune response, consequently enhancing the effectiveness of cancer therapies.93,99 Additionally, nanomaterials show therapeutic potential by regulating CAF roles in immune responses, angiogenesis, and tumor tissue stiffening.96,129 For example, certain nanomaterials influence the physical and chemical dynamics of the tumor microenvironment. They disrupt angiogenesis in tumors and regulate the secretion of growth factors by tumor-associated fibroblasts, effectively inhibiting tumor growth and metastasis.101,103 Despite challenges such as targeting precision and potential off-target effects, current research emphasizes improving nanomaterial design to overcome these issues.130 Overall, nanomaterial and CAFs interactions deepen our understanding of the TME’s complexity and pave the way for innovative anticancer strategies. However, further research and clinical trials are essential to optimize the use of nanomaterials and ensure their safety in clinical applications.

Nanoscale Drug Delivery Systems Targeting CAFs for Cancer Treatment

Although nanomedicine delivery systems have more advantages than traditional drug therapy.131–133 Nanomedicine faces numerous challenges in entering tumors,134 especially its therapeutic effects in solid tumors and proliferative connective tissue tumors are limited.135 Therefore, it is necessary to take measures to enhance the penetration and permeability of nanomedicines to strengthen drug delivery capability.136–138 In this regard, we have introduced some enhanced delivery system approaches (Figure 4).

Figure 4 Mechanisms of Tumor Targeting Mediated by Nanomedicine. (A) Various types of nanoparticles (NPs), including liposomes, micelles, mesoporous silica NPs, dendrimers, and gold NPs, serve as versatile carriers for drug delivery. (B) Functionalization with ligands such as antibodies, hyaluronic acid, peptides, and folic acid enhances their specificity for CAFs and other TME components. (C and D) Tumor targeting by nanomedicine is mediated through both passive and active mechanisms. Passive targeting exploits the enhanced permeability and retention effect, allowing nanoparticles to accumulate in tumor tissues with leaky vasculature and impaired lymphatic drainage. Active targeting, on the other hand, uses ligand-functionalized nanoparticles to specifically bind to receptors, such as GPCR, on tumor cells or CAFs, facilitating receptor-mediated internalization and endosomal delivery. These mechanisms enhance precision in drug delivery and improve therapeutic efficacy in modulating the TME. Reproduced from Chang Y, Ou Q, Zhou X, et al. Mapping the intellectual structure and landscape of nano-drug delivery systems in colorectal cancer. Front Pharmacol. 2023;14:1258937. https://creativecommons.org/licenses/by/4.0/.134.

Gene-Related Drug Delivery Systems Targeting CAFs

Traditionally, studying DNA and RNA is fundamental approach in biology. In one study, researchers invented a polymer called Polymeric Vinyl Resin (PVR) and combined it with plasmids encoding Relaxin (RLN) to form lipid nanoparticle complexes (LPPR), aiming to enhance gene transfer efficiency and reduce toxicity, this approach resulted in inhibiting CAF proliferation and tumor growth.139 5-Fluorouracil (5-FU) is a DNA synthesis inhibitor, blocks the normal thymine nucleotide biosynthesis pathway, preventing tumor cells and CAFs from growing and dividing normally, although it also affects normal cells. However, Handali et al in the study found that a new folate liposome can more effectively deliver fluorouracil to cancer cells and reduce toxicity.140 Similarly, in another new study, Jain et al discovered that certain microRNAs can enhance the sensitivity of colorectal cancer radiotherapy by regulating tumor cell apoptosis, DNA damage repair pathways.115 Meanwhile, in a study by Sheng et al, a CAF-targeted poly (lactic-co-glycolic acid) (PLGA) nanoemulsion was used to simultaneously deliver doxorubicin (DOX) and small interfering RNA (siRNA) targeting hepatocyte growth factor (HGF) for chemotherapy and gene therapy. The results were surprising to find that the delivered siRNA reduced the expression of HGF in the remaining CAFs, thus overcoming the chemotherapy-induced upregulation of HGF mRNA and preventing the increment of CAFs through an autocrine HGF closed loop.82 Due to these synergistic effects, tumor proliferation, migration, and invasion were significantly inhibited, and tumor permeability was significantly improved. Furthermore, it is well known that siRNA is a type of small RNA, and inhibits gene expression by interfering with the stability and translation of targeted mRNA molecules. At present, many studies have proved that siRNA can be encapsulated into cells by liposomes to inhibit the gene expression of tumor cells,141,142 but there are only a few studies that have shown that siRNA may also act on CAFs to inhibit the biological function expression of CAFs,143,144 so we look forward to more research in this field in the future. Lastly, in a special study, researchers discovered a dual-labeled nanoprobe based on small extracellular vesicles (sEVs) that can be utilized for tumor detection and diagnosis.145 This nanoprobe can also serve as a potent tool for studying the biological behaviors of nanosystems in drug delivery, showing significant potential for future applications.

Small Molecule Loaded Drug Delivery System

At present, many small molecule drugs have been used to treat cancer and improve the TME,16 indicating that small molecule drugs have many advantages in targeting CAFs and cancer immunotherapy. Here, we summarize the latest small molecule-loaded drugs for targeted treatment of CAFs. Nano drug carriers, such as Cellax-DTX nanoparticles, can deliver chemotherapy drugs with high specificity to CAFs, promoting CAF apoptosis and modulating TME. Moreover, Leopoldo Sitia et al used functionalized H-ferritin nanocages and combined them with fragments of FAP antibodies to prepare highly affinity drug carriers.146 Duan designed a dual-targeted liposome-hybrid micelle system (RPM@NLQ) triggered by matrix metalloproteinase (MMP), sequentially delivering quercetin (Que) and paclitaxel (PTX) to target CAFs, thereby downregulating Wnt16 expression in CAFs to enhance fibrosis improvement.147 Furthermore, a special nanoemulsion (NE) system can deliver anti-fibrotic drug fraxinellone (Frax) to CAFs, meanwhile researchers also noted that Frax NE combined with tumor-specific peptide vaccines may be an effective and safe strategy.145 Other small molecule compounds like superparamagnetic iron oxide nanoparticles (SPIONs) could target fibroblast growth factor 2 (FGF2) precursors in CAFs to inhibit their production, while also enhancing the efficacy of gemcitabine.148 Admittedly, Clara et al’s study demonstrated that hydrogen peroxide plays a crucial role in the interaction between gold-iron alloy nanoparticles and CAFs.149 Interestingly, some macromolecules have also been found effective. For example, the nano-composite hydrogel invented by Liu et al150 and the peptide-Doxorubicin (GFLG-DOX) conjugate of polyamidoamine (PAMAM) dendritic macromolecules invented by Rashed M et al,151 both can enhance the penetration and efficacy of chemotherapy drugs without damaging healthy tissues.150

Other Immunotherapy Strategies Targeting CAFs

Targeting CAFs is an important part of the cancer treatment process. Nowadays, researchers are exploring the use of antibodies or other ligands to specifically bind to receptors on the surface of CAFs, thereby inducing their apoptosis or inhibiting their growth. For example, Liang et al used a peptide-assembled nanosystem to effectively inhibit the metastasis of CAFs and prostate cancer.152 Additionally, there are methods to reprogram CAFs, for example, CAF metabolic reprogramming to control glucose uptake and lactate production to design specific drug-targeting strategies.94,153 For instance, Theivendran S et al used DMON-P to reprogram CAFs, downregulate CAF biomarkers, and effectively deliver Dox to inhibit tumor growth.154 Meanwhile, multiple studies have found that DNA-targeted vaccines have multiple biological advantages,155 for example, Geng et al invented a vaccine targeting tumor cells and FAPα and tumor cell antigen survivin, which can specifically eliminate CAFs, regulate the tumor microenvironment, and enhance T cell-mediated anticancer effects.156 Regarding vaccines, in a recent study, Hu et al used CAFs as antigens to create vaccines, which stimulate the body to generate an immune response targeting CAFs, thus attacking tumor cells. Finally, their experiments were successful both in vitro and in vivo, so their result indicate that using CAFs as antigens to make vaccines is a feasible cancer treatment method, worthy of further research and exploration.144 Moreover, introducing activated T cells into the tumor site has been shown to reduce tumor growth. These T cells specifically recognize and attack CAFs, contributing to the inhibition of tumor progression.141 Liposomes are also common carriers targeting CAFs. For instance, Li et al conjugated scFv to liposomes to utilize the high-affinity binding capability of anti-tumor specific monoclonal antibodies, allowing liposomes to better penetrate tumor tissues and achieve higher therapeutic efficacy, enhancing colorectal cancer treatment.157 Moreover, we also find a new type of co-loaded liposome targeting the insulin receptor (IR) can specifically reduce CAF activity to inhibit tumors.158 In the study of Lee et al, they chose an anti-fibrotic drug, nintedanib, to reduce CAFs activation and proliferation, resulting in blocking the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and reducing its secretion of IL-6 levels to inhibit CAFs.159

Conclusion and Future Research Directions

Previous research indicates that CAFs not only generate extracellular matrix components that make up tumor stroma but also release growth factors, chemokines, exosomes, and metabolites, influencing all tumor characteristics, including drug treatment response.160 As our understanding of CAFs evolves with ongoing scientific research, broader avenues for targeted immunotherapy based on their characteristics are emerging. Several studies suggest a correlation between PD-L1 expression levels and the degree of CAF enrichment. Specifically, certain CAFs can suppress T-cell activity by secreting PD-L1, aiding tumor cells in evading immune system attacks. Therefore, research on the relationship between PD-L1 and CAFs is crucial for understanding the regulatory mechanisms of the tumor immune microenvironment and developing more effective tumor therapies.161–163 In addition to their role in immune suppression, CAFs can also directly influence tumor cell behavior and characteristics by secreting growth factors, activating protein receptor signaling pathways, and regulating gene expression. Therefore, targeting these pathways is crucial for treating cancer. As shown in Table 2 below, we have summarized some current drugs and treatments that aim to inhibit CAFs.

Table 2 Drugs for Targeting CAFs in Preclinical and Clinical Trials

Although in the past few decades, an increasing number of new drugs and treatments have emerged for targeted therapy of CAFs, and the advantages of using nanoplatforms for targeted cancer treatment of CAFs have been magnified, there remains a significant challenge in translating novel nanoplatforms into clinically usable applications. So far, we have observed that the use of responsive biomaterials in the design and preparation of nanomedicines can achieve targeted effects on the tumor microenvironment and CAFs. The growing potential of this approach in clinical applications indicates that it may become a new trend in the future.174 In fact, in addition to the previously mentioned targeted therapies, new treatment methods are emerging, such as using engineered exosomes with powerful intercellular communication, payload delivery, penetration, and targeting capabilities, making them potent tools for developing next-generation personalized nanomedicines for treatment and diagnosis.175 Targeting tumor-associated macrophages and other cells is also an emerging direction for cancer treatment.176 Future research should focus on several areas. Firstly, developing more precise and selective nanomedicine delivery systems.177–179 Specifically, if these drug delivery systems can respond to specific stimuli in the tumor microenvironment such as pH, enzymes, or temperature, improving the targeting accuracy and release kinetics of therapeutic agents.180–182 In addition, these specificities can minimize systemic toxicity and maximize therapeutic effects on cancer cells and CAFs.183 Secondly, exploring the synergistic effects of combining CAF-targeted nanomedicines with other treatment modalities, such as immunotherapy, chemotherapy, gene therapy, and photodynamic therapy, can lead to more effective cancer treatments.179,184–187 For instance, we can integrate gene editing technology and metabolic reprogramming strategies into nanomedicine platforms,188,189 which can directly modify the genetic and metabolic characteristics of CAFs, thereby disrupting their tumor promoting function and enhancing the efficacy of other therapies. For patients, using combination therapy can help overcome drug resistance, enhance immune system activation, and launch multi-faceted attacks on tumor cells, improving their clinical treatment outcomes.94 The third is to strengthen the connection between basic research and clinical trials, accelerate the development and clinical use of new targeted drugs.190,191 Finally, from the perspective of nanomaterials, multifunctional nanomaterials can improve the accuracy of drug delivery by simultaneously targeting multiple aspects of the tumor microenvironment, thereby reducing side effects and improving overall therapeutic outcomes.93,133 Such nanomaterials could simultaneously target CAFs, deliver therapeutic agents, and regulate immune responses. We hope to see their development and clinical application in the near future. Moreover, we recently discovered that some studies have explored the application of traditional Chinese medicine ingredients in targeted delivery, which represents another effective treatment method.192,193 So, if nanocarriers can be effectively used to deliver traditional Chinese medicine components with inherent therapeutic properties to CAFs,194,195 this may provide the possibility of providing novel therapeutic approaches with synergistic effects. However, due to limited current research, there is not sufficient data to extensively discuss this system. We look forward to more research in the future to demonstrate the advantages of using traditional Chinese medicine delivery systems to target CAFs for cancer immunotherapy.

Abbreviations

CAFs, Cancer-associated Fibroblasts; TME, Tumor Microenvironment; CRC, Colorectal Cancer; ECM, Extracellular Matrix; myCAFs, myofibroblasts; iCAFs, inflammatory CAFs; apCAFs, antigen-presenting CAFs; MSCs, marrow-derived mesenchymal stem cells; TGFβ, Transforming Growth Factor Beta; IL-6, Interleukin-6; α-SMA, α-Smooth muscle actin; FAP, Fibroblast Activation Protein; PDGFR, Platelet-Derived Growth Factor Receptor; FN, fibronectin; LN, laminin; MMPs, matrix metalloproteinases; EPCAM, epithelial cell adhesion molecule; SGR, synovial glycoprotein; MBL, Mannose-binding lectin; OPN, osteopontin; HGF, hepatocyte growth factor; PADC, pancreatic ductal adenocarcinoma; TNF-α, Tumor Necrosis Factor-alpha; MDSCs, myeloid-derived suppressor cells; PD-L1, programmed death ligand 1; AuNPs, Gold nanoparticles; TRF, Transferrin Receptor; MMP-2, Matrix Metalloproteinase-2; PVR, Polymeric Vinyl Resin; RLN, Relaxin; LPPR, lipid nanoparticle complexes; 5-FU, 5-Fluorouracil; PLGA, poly (lactic co-glycolic acid); DOX, deliver doxorubicin; sEVs, small extracellular vesicles; MMP, matrix metalloproteinase; Que, quercetin; FGF 2, fibroblast growth factor 2; NE, nanoemulsion; SPIONs, superparamagnetic iron oxide nanoparticles; PAMAM, polyamidoamine; IR, insulin receptor; TKI, tyrosine kinase inhibitor; VEGFR, Vascular Endothelial Growth Factor Receptor; PAI-2, plasminogen activator inhibitor 2; HIF 1, Hypoxia inducible factor 1; ICI, immune checkpoint inhibitor; ZBP1, Zinc finger binding protein 1; ROS, reactive oxygen species.

Data Sharing Statement

The data in the manuscript is available. All data can be obtained by contacting the corresponding author.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by Natural Science Foundation of Sichuan Province (2023NSFSC1552), the University-Level Natural Science Foundation General Project of Chengdu Medical College, (2024CDYXY-01), the Clinical Science Research Foundation of Chengdu Medical College & the First Affiliated Hospital of Chengdu Medical College (24LHLNYX1-08), Clinical Science Research Foundation of Chengdu Medical College & the Nanbu People’s Hospital (24LHFBM1-04) and Clinical Science Research Foundation of Chengdu Medical College & the Third Affiliated Hospital of Chengdu Medical College (24LHFYSZ1-41).

Disclosure

The authors declare that there are no competing interests associated with this work.

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