Nanomaterials in cancer immunotherapy: targeting cancer-associated fibroblasts

Abstract

Emphasizing the significance of cancer-associated fibroblasts (CAFs), non-malignant yet pivotal players within the tumor microenvironment (TME), this review illuminates the role of inflammatory subtype (iCAF) as catalysts in cancer proliferation, metastasis, and therapeutic resistance. Given their paramount importance, targeting CAFs emerges as a robust strategy in the evolving landscape of cancer immunotherapy. Nanomaterials, distinguished by their unique features and malleability, hold considerable promise in biomedicine, especially in the precision-oriented domain of cancer therapy. Their aptitude for modulating immune responses, amplifying drug efficacy through precise delivery, and discerningly focusing on cells within the TME situates nanomaterials as formidable tools to transcend the boundaries set by conventional treatments. This review scrutinizes the convoluted interplay among CAFs, immune cells, and tumor cells within the TME. It further showcases widely utilized nanomaterials in cancer management. We underscore the potential of nanoscale drug delivery systems directed at CAFs, underscoring their transformative power in revolutionizing cancer therapies, enhancing precision, and culminating in improved patient outcomes.

Introduction

Cancer remains one of the most formidable health challenges worldwide (Li et al. 2024a), with TME playing a critical role in cancer progression and resistance to therapy (Xiang et al. 2022; Hu et al. 2020a). Among the various components of the TME, CAFs have emerged as key players in facilitating tumor growth and metastasis. CAFs contribute to numerous aspects of tumor biology, including promoting tumor growth and metastasis, enhancing drug resistance, remodeling the TME, and inducing immunosuppression (Burley et al. 2022). For instance, CAFs have been shown to transfer exosomes to colorectal cancer cells (CRC), significantly increasing the levels of miR-92a-3p, which leads to metastasis and chemotherapy resistance in CRC patients (Hu et al. 2019). These cells not only support the structural integrity of tumors through extracellular matrix (ECM) deposition, but also modulate immune responses, thus contributing to a complex network of interactions that promote tumor survival and resistance to treatments (Lu et al. 2023; Piersma et al. 2020). Furthermore, the existence of different subtypes and phenotypes of CAFs across different tumors complicates the development of universal targeting strategies. In recent years, the heterogeneity of CAFs has emerged as a pivotal factor in cancer progression and therapy resistance (Montazersaheb et al. 2024). These cells, once considered uniform, are now understood to exhibit diverse subtypes—each with distinct molecular signatures and roles within the TME. This complexity underscores the necessity of developing targeted therapies that address specific CAF functions to effectively combat cancer (Chen et al. 2021). Given their pivotal role, CAFs represent a promising target for therapeutic intervention in cancer immunotherapy.

Recent advances in nanotechnology have opened new avenues for cancer treatment, particularly through the development of nanomaterials that can be precisely engineered to target specific cellular functions within the TME (Liu et al. 2023a; Liang et al. 2024a; Gu et al. 2024). Nanomaterials offer unique properties, such as small size, large surface area to mass ratio, and the ability to encapsulate or conjugate with various therapeutic agents, making them ideal candidates for overcoming some of the limitations associated with conventional cancer therapies (Rosic 2024; Li et al. 2024b). Different types of nanomaterials, including organic and inorganic varieties, offer distinct physicochemical properties that provide significant advantages in drug delivery and treatment (Liu et al. 2022a; Hu et al. 2024a; Kimiz-Gebologlu and Oncel 2022; Huseynov 2024). These materials can be engineered to target CAFs specifically, modifying the TME to enhance anti-tumor immunity (Gong et al. 2019; Wu et al. 2024). Targeting CAFs with nanomaterials disrupts the fibrotic stroma, reduces ECM deposition, and alleviates the immunosuppressive environment (Cheng et al. 2024a). This disruption not only enhances the infiltration of immune cells and therapeutic agents into the tumor core but also facilitates improved treatment efficacy (Zhu et al. 2022). Additionally, nanomaterials can be designed to carry immunomodulatory agents, promoting the activation and proliferation of immune cells within the TME (Tong et al. 2022). For example, nanoparticles targeting CAFs can dismantle the immunosuppressive stroma, allowing for increased infiltration and activity of cytotoxic T lymphocytes, thereby boosting immune responses against the tumor (Han et al. 2022). Specifically, the targeting of CAFs with nanomaterials presents an innovative approach to modulate the tumor stroma, potentially enhancing the efficacy of immunotherapeutic agents (Wu et al. 2024; Jian et al. 2024).

Nanomedicine, as a leading-edge approach in cancer therapy, offers targeted delivery systems that reduce systemic toxicity and improve therapeutic outcomes (Montazersaheb et al. 2024; Huseynov 2024; Liu et al. 2019a). In conclusion, nanomedicine targeting CAFs holds significant promise for advancing cancer immunotherapy (Wang et al. 2023a). By leveraging the unique properties of nanomaterials, these systems can precisely regulate the TME, thereby enhancing both local and systemic immune responses (Hong et al. 2025; Liu et al. 2024a). This approach has the potential to improve treatment outcomes, survival rates, and the quality of life for cancer patients.

Method

We conducted a comprehensive search of the PubMed database for English-language publications from 2019 to 2024, using the keywords 'cancer-associated fibroblasts (CAFs)', 'nanomedicine', 'drug delivery', 'tumor microenvironment (TME)', and 'cancer immunology'. This search yielded a total of 921 articles. Following a thorough screening process, studies lacking relevance to CAFs, nanomedicine, and TME interactions were excluded. Based on predefined inclusion criteria, 394 articles were selected for detailed analysis, focusing on recent advancements in CAF-targeting strategies, the role of nanomaterials in drug delivery, and their interactions within the TME and cancer immunotherapy.

What is CAF?

CAF subtypes: origins, functions, and their role in cancer therapy

CAFs arise from various cellular origins, with one common source being normal fibroblasts recruited by tumor cells, which are subsequently converted into CAFs (Rimal et al. 2022). Additionally, CAFs can emerge from the transformation of other cell types, such as endothelial and epithelial cells, mesenchymal stem cells, and adipocytes, as well as from the differentiation of tumor stem cells (Kobayashi et al. 2022; Zhang et al. 2023a; Tang et al. 2022). The origin of CAFs may also be influenced by physiological conditions, tumor type, environmental factors, and other variables (Sahai et al. 2020; Santi et al. 2018). For example, studies have shown that in breast cancer, adipocytes can undergo dedifferentiation into CAFs (Jotzu et al. 2010). Interestingly, a lack of certain substances in specific environments can also induce CAF differentiation (Ferrer-Mayorga et al. 2017). For instance, Jerome Thiery’s research highlights that deficiencies in vitamins A or D can promote CAF differentiation in some cases (Thiery 2022). However, further research is needed to fully explore the various origins of CAFs under different conditions.

Moreover, different subtypes of CAFs exhibit distinct biological characteristics and functions (Huang et al. 2023; Cortez et al. 2014), such as invasive CAFs, immunosuppressive CAFs, stromal CAFs, and degenerative CAFs. Invasive CAFs contribute to tumor invasion and metastasis (Yin et al. 2024), immunosuppressive CAFs help tumors evade immune surveillance (Pradip et al. 2021), stromal CAFs play a key role in constructing the tumor microenvironment (Dong et al. 2024), and degenerative CAFs are primarily associated with tumor drug resistance (Zhu et al. 2018). Generally, CAFs are often categorized into three major groups: myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) (Wang et al. 2024a; Maia and Wiemann 2021; Foster et al. 2022). Myofibroblastic CAFs (myCAFs) are characterized by the expression of alpha-smooth muscle actin (α-SMA) and are primarily involved in matrix deposition and remodeling (Li et al. 2024c; Geng et al. 2021). Inflammatory CAFs (iCAFs) secrete cytokines and chemokines that modulate immune responses, marked by the expression of S100A4 (Friedman et al. 2020; Santolla et al. 2021). Antigen-presenting CAFs (apCAFs) have recently been identified for their capability to present antigens and interact with T cells (No Author 2022; Huang et al. 2022a; Kerdidani et al. 2022), although their markers are still being explored (Yamashita and Kumamoto 2024; Guo and Xu 2024). iCAFs contribute to creating an immunosuppressive environment that supports tumor growth by secreting inflammatory mediators (Guo and Xu 2024; Monteran and Erez 2019), while myCAFs enhance tumor stiffness and fibrosis, affecting drug penetration and efficacy (Bates et al. 2023). apCAFs represent a potential target for immunotherapy due to their role in modulating T-cell activity within the TME (Kerdidani et al. 2022). Understanding these CAF subtypes and their unique role in TME allows us to design more effective nanomaterial-based therapies (Rosic 2024; Singh et al. 2024a; Wang et al. 2024b; Peng et al. 2024), for example, we can develop nanoparticles that simultaneously target multiple CAF subtypes or combine CAF targeting with direct anticancer effects (Huang et al. 2024a). Specifically, a new nanoparticle could be designed to carry both TGF-β inhibitors (for myCAFs) and siRNA, a cytokine for iCAFs (D’Aversa et al. 2024; Yang et al. 2023a; Wu et al. 2023). We can even tailor the nanoparticle treatment regimen to the patient based on the CAF population that dominates the patient's tumor, thus achieving personalized treatment (Tian et al. 2024; Su et al. 2023).

Interestingly, some studies suggest that balancing the number of CAF subgroups may offer important clinical benefits (Foster et al. 2022). This indicates the potential for patient-specific treatments based on the number and type of CAF subpopulations (Hu et al. 2021). Different CAF subtypes exist in various tissues and organs, and understanding their unique characteristics and functions is essential for developing new strategies for targeted therapies (Helms et al. 2022). The presence of multiple CAF subtypes within different tumors and tissues suggests that these cells may play diverse roles in various diseases (Houthuijzen et al. 2023; Sung and Lee 2024). Gaining deeper insights into the functions of CAF subtypes will contribute to our understanding of the tumor microenvironment and its regulatory mechanisms, offering potential new directions for targeted cancer therapy (Fig. 1) Yang et al. 2023b.

Fig. 1

^© 2023 by the authors

CAF subtypes: origins, functions, and their role in cancer therapy. The illustration depicts the diverse cellular origins, heterogeneity, and functional roles of CAFs within the tumor microenvironment. CAFs can originate from various cell types, including epithelial cells, endothelial cells, mesothelial cells, adipocytes, smooth muscle cells, or differentiate from bone marrow-derived mesenchymal stem cells. The figure also highlights three major CAF subtypes: myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs), which are involved in extracellular matrix remodeling, cytokine secretion, and immune modulation, respectively. These CAF subtypes display distinct functions, either promoting or restraining tumor progression, reflecting the phenotypic and functional heterogeneity of CAFs. Reproduced fromYang et al. 2023b, Copyright

CAF markers: key players in tumor progression and therapy

CAFs and their associated markers play a crucial role in tumor progression, particularly through their varied biological functions in the TME (Pan et al. 2024). Understanding these markers is essential for advancing our comprehension of cancer immunotherapy. Currently, it is widely accepted that CAF markers hold significant clinical relevance (Simon and Salhia 2022). For example, these markers are valuable tools for identifying and tracking the development of tumors (Gadd et al. 2022). Clinicians can use these markers to diagnose tumors and assess disease severity by detecting them in blood or tissue samples (Li et al. 2018a). Additionally, CAF markers can help predict a tumor's response to different treatments and monitor the effectiveness of therapies. Given this, the clinical potential of CAF markers is promising (Zhang et al. 2023b).

The discovery of CAF markers has been a challenging and ongoing process. α-Smooth muscle actin (α-SMA), first identified in the 1970s by Gabbiani and colleagues in studies on wound healing, remains one of the most widely recognized markers of CAFs and is commonly used for their identification (Tarbit et al. 2019; Muchlińska et al. 2022). However, recent research indicates that α-SMA-positive CAFs may exhibit both pro-tumorigenic and anti-tumorigenic properties (Shinde et al. 2017; Elewa et al. 2024). Another classic marker is fibroblast activation protein (FAP), a membrane protein discovered in the early 1990s in interstitial cells and certain cancers (Fitzgerald 2024). Platelet-derived growth factor receptor (PDGFR), highly expressed in CAFs and linked to their activation and tumor-promoting roles, was identified by Jan-Åke Gustafsson and Charles-Henri Heldin during molecular cloning experiments in 1978 (Matsui et al. 1989).

With advancements in detection techniques, scientists have identified an array of CAF markers using methods like single-cell sequencing (Lavie et al. 2022). Additional markers include Vimentin, fibronectin (FN), laminin (LN), matrix metalloproteinases (MMPs), epithelial cell adhesion molecule (EPCAM), synovial glycoprotein (SGR), and mannose-binding lectin (MBL) (Hernández-Jiménez et al. 2022; Nurmik et al. 2020; Mao et al. 2021; Zhao et al. 2023). Interestingly, in breast cancer-associated fibroblasts, specific genes such as NOTCH3 and HES4 have been found to serve as markers involved in CAF self-renewal and proliferation (Bartoschek et al. 2018). This discovery suggests a potential new method of integrating gene technology with these specific markers, offering a novel direction for future research.

While many new markers have been identified, the number of known fibroblast biomarkers remains limited (Xia et al. 2024). A key challenge moving forward is distinguishing between normal fibroblasts, CAFs, and different CAF subtypes using simple markers (Nurmik et al. 2020). This distinction is crucial for understanding CAF heterogeneity and improving targeted therapies. Hopefully, further research will provide answers to these challenges in the near future.

The multifaceted role of cancer-associated fibroblasts in tumor progression and treatment implications

The relationship between CAFs, tumors, and tumor cells is complex and has significant implications for patient prognosis (Koumpis et al. 2024; Wang et al. 2024c). Studies suggest that the quantity and activity of CAFs are closely correlated with the prognosis of cancer patients (Qin et al. 2023). However, the impact of CAFs on tumor development and prognosis is multifaceted, influenced by various factors (Caramelo et al. 2023). During cancer progression, CAFs interact with tumor cells by expressing extracellular signaling molecules such as osteopontin (OPN) and hepatocyte growth factor (HGF), which influence tumor cell proliferation, invasion, and migration (Ping et al. 2021). These interactions demonstrate how CAFs can significantly shape the TME.

In the TME, CAFs regulate tumor growth through several mechanisms, including metabolic modulation. They affect processes such as glucose regulation and pH balance, and even mitochondrial function, contributing to the energy metabolism of tumor cells (Owen et al. 2022). Additionally, mechanical forces generated by CAFs can alter tumor cell movement and morphology by activating cytoskeletal systems and intracellular signaling pathways, potentially accelerating tumor spread (Sharbeen et al. 2021). Exosomes, small extracellular vesicles secreted by cells, are critical mediators of cellular communication and tissue homeostasis (Pedersen et al. 2024). CAF-derived exosomes, in particular, play an essential role in influencing tumor behavior (Li et al. 2017; Shi et al. 2023). For example, Piwocka and colleagues found that exosomes secreted by CAFs carry microRNA-296-3p, which promotes malignant behaviors like proliferation, migration, invasion, and drug resistance in ovarian cancer cells. This suggests that microRNA-296-3p could serve as both a diagnostic marker and a therapeutic target (Sun et al. 2024a). Similarly, Zhang et al. discovered that miR-522, delivered via exosomes, enhances tumor cell resistance to chemotherapy and inhibits ferroptosis in gastric cancer cells by targeting ALOX15, thereby regulating lipid peroxidation (Zhang et al. 2020a). Their findings highlighted a novel intercellular pathway involving USP7, hnRNPA1, exo-miR-522, and ALOX15, which influences chemotherapy sensitivity through lipid peroxidation. Admittedly, CAFs contribute to the dense fibrotic stroma characteristic of many solid tumors (D’Aversa et al. 2024; Norton et al. 2020). This fibrosis not only physically impedes drug penetration, but also actively sequesters chemotherapeutic agents, significantly lowering their bioavailability and efficacy (D’Aversa et al. 2024). CAFs are prolific producers of growth factors like TGF-β, which not only enhances tumor cell proliferation and survival but also contributes to the creation of an immunosuppressive tumor microenvironment that shields the tumor from immune cell attack (Yang et al. 2023a; Perez-Penco et al. 2024). So recognizing the multifaceted roles of CAFs in mediating therapy resistance provides a strong rationale for developing CAF-targeted therapies (Timperi et al. 2024). Strategies that disrupt CAF functions or modify their interactions with tumor cells and other TME components could significantly enhance the efficacy of both conventional and immune-based cancer therapies (Xue et al. 2024; Eigentler et al. 2024). Conversely, tumors and tumor cells can influence CAF activation and function (Sung and Lee 2024). CAFs can be activated through direct interactions with tumor cells or via signaling pathways such as the Notch pathway. Once activated, CAFs remodel the ECM, which further amplifies their activation in a positive feedback loop (Park et al. 2020). Tumor cells may also induce the "reverse Warburg effect" in CAFs, enhancing glycolytic activity to meet the metabolic demands of the tumor. In pancreatic ductal adenocarcinoma (PDAC), for instance, tumor cells induce autophagy in CAFs, leading to the release of non-essential amino acids like alanine (Yang et al. 2023b). These amino acids support cancer cells by fueling the tricarboxylic acid (TCA) cycle and lipid biosynthesis, aiding tumor growth and survival (Melissari et al. 2020).

In conclusion, the intricate relationship between CAFs, tumors, and tumor cells underscores the importance of CAFs as both therapeutic targets and integral components of cancer treatment strategies (Park et al. 2020). This interconnectedness suggests that future therapeutic approaches should be tailored based on the specific tumor type and CAF subtype, rather than relying on a one-size-fits-all approach (Li et al. 2021a; Esposito et al. 2024). Personalizing treatments in this way will help address the unique challenges posed by CAF–tumor interactions and improve the effectiveness of cancer therapies (Toledo et al. 2022; Jia et al. 2024a).

Cancer-associated fibroblasts: key regulators of the tumor microenvironment and tumor progression

The tumor microenvironment (TME) is a complex ecosystem composed of various cellular and non-cellular components, including ECM, blood vessels, immune cells, and tumor-associated cells (Timperi et al. 2024). CAFs are key players in this environment, interacting extensively with tumor cells and significantly contributing to tumorigenesis and progression (Schütz et al. 2023). Current research shows that CAFs can influence immune evasion by either activating or inhibiting the immune system (Peng et al. 2024; Li et al. 2023), as well as promoting angiogenesis, regulating inflammatory responses, and remodeling the ECM (Zeng et al. 2023a; Luo et al. 2022). These functions illustrate the crucial role of CAFs in shaping the TME, making the interaction between CAFs and the TME an essential focus for cancer research (Thinyakul et al. 2024).

CAF interactions within the TME are reciprocal. CAFs regulate the TME by secreting growth factors, chemokines, and other molecules that facilitate tumor formation and progression (Han et al. 2020a). For instance, CAFs secrete signaling molecules that remodel the ECM and reprogram metabolic pathways within the TME. This metabolic reprogramming supports tumor cell survival and growth, while the remodeling of the ECM enhances the structural environment necessary for tumor expansion (Cirri and Chiarugi 2012). Moreover, CAFs engage in transmembrane signaling with other cells in the TME, influencing disease progression through pathways such as PDGF, IL-6, and TNF-α (Fang et al. 2023; Piwocka et al. 2024). These chemokines attract and recruit immune cells and other cell types to the tumor site, further contributing to tumor growth and metastasis.

In recent years, the role of exosomes in the TME has gained attention, particularly in relation to cancer progression and inflammation (Liu et al. 2021). Exosomes are extracellular vesicles that facilitate communication between CAFs and tumor cells. These vesicles carry proteins, RNA, and other bioactive molecules that influence tumor development (Hajialiasgary Najafabadi et al. 2024; Cai et al. 2023). For example, research by Sun et al. demonstrated that exosomal non-coding RNAs (ncRNAs) secreted by CAFs contribute to the formation of the colorectal cancer microenvironment and are linked to resistance mechanisms in CRC patients undergoing radiotherapy (Sun et al. 2023). Exosomal communication is thus a critical pathway by which CAFs can influence tumor progression and treatment resistance.

Additionally, the TME influences the biological characteristics and functions of CAFs (Zhang et al. 2024a; Barros da Silva et al. 2024). For instance, environments with high concentrations of hyaluronic acid (HA) or oxidative stress can stimulate CAFs to exhibit more aggressive, tumor-promoting behavior (Donelan et al. 2022). These environmental factors can alter CAF activity, enhancing their ability to support tumor growth and metastasis. However, despite these insights, many uncertainties remain regarding how different TMEs affect CAF behavior (Liu et al. 2019b; Xu et al. 2023). Future research is expected to provide breakthroughs in understanding these complex interactions, which could lead to novel therapeutic strategies targeting CAFs and their interactions within the TME.

The role of cancer-associated fibroblasts in immune regulation within the tumor microenvironment

Immune cells are an important part of the tumor microenvironment and play complex roles in the development of cancer. These roles may sometimes have time-dependent dynamic transitions, such as the polarization of macrophages into different physiological phenotypes under different circumstances (Huang et al. 2021). In many cases, CAFs contribute to immune suppression, hindering the immune system's ability to attack tumor cells (Laplagne et al. 2019). This interaction between CAFs and immune cells is crucial for understanding how the tumor microenvironment supports cancer growth and evades immune surveillance. CAFs can interact with a variety of immune cells, including T cells, helper T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells (MDSCs) (Thiery 2022; Huang et al. 2022a; Sharbeen et al. 2021; Tsoumakidou 2023). One prominent example of this interaction is how CAFs inhibit T cell activation. In a recent study, Ying et al. demonstrated that CAFs can express inhibitory receptors such as programmed death ligand 1 (PD-L1), which binds to PD-1 on T cells. This interaction effectively dampens the activation of T cells, allowing tumor cells to evade immune surveillance and proliferate unchecked (Ying et al. 2023). Similarly, Zeng et al. found that macrophages expressing M2 phenotype-related genes could enhance chemotherapy resistance in both CAFs and breast cancer cells, further promoting tumor survival and progression (Zeng et al. 2023b). In addition to T cells and macrophages, CAFs regulate cancer cell proliferation and migration by secreting extracellular signaling molecules such as growth factors and chemokines (Yavuz et al. 2020). These molecules recruit immune cells to the tumor site, where they often contribute to an immunosuppressive environment rather than promoting an effective anti-tumor response. However, the impact of CAFs on immune cells is not uniform (Jia et al. 2024b). Different CAF subtypes can influence the distribution and activity of immune cells in distinct ways, underscoring the importance of subtype-specific research in understanding the diverse roles of CAFs within the TME (Schütz et al. 2023).

Recent advances in spatial transcriptomics have provided deeper insights into the physical and functional relationships between CAFs and immune cells within tumors (Li et al. 2024d). For instance, Chen et al. used this technology to study lung cancer, revealing distinct distribution patterns of different cell types within the TME. They found that CAFs and malignant tumor cells often cluster together at the tumor core, while immune cells, including macrophages and dendritic cells, are more commonly found at the tumor's periphery (Chen et al. 2023a). This spatial arrangement highlights the dynamic interplay between CAFs and immune cells and may help explain how immune suppression is maintained in certain regions of the tumor.

Nanomaterials and tumor targeted therapy

Classification of nanomaterials

In recent years, the rapid development of nanomaterials and their increasing applications in medicine have made medical nanomaterials a significant area of research (Lai et al. 2024; Meng et al. 2024). This review aims to explore various nanomaterials utilized in modern medicine, including nanoparticles, biomimetic nanoparticles, inorganic nanomaterials, organic–inorganic hybrid nanomaterials, and conventional nanomaterials, as well as their specific roles in biological systems (Table 1). At the same time, we also aim to clearly demonstrate the advantages and limitations of these nanomaterials in CAF targeting (Table 2; Fig. 2) Eleraky et al. (2020).

Table 1 Classification of nanomaterials

Table 2 Advantages and limitations of nanomaterials for CAF targeting

Fig. 2

^© 2020 by the authors

Advancements in medical nanomaterials. Nanosystems can be classified into inorganic and organic types, based on their matrix characteristics and the materials they are composed of. This figure also focuses on the specific roles these nanomaterials play in managing bacterial biofilms. Furthermore, the title conveys the diversity of nanomaterial types discussed and their significant impact on biological systems. Reproduced from Eleraky et al. (2020), Copyright

Tumor cells are influenced by various factors, including the TME and CAFs. Nanomaterials have shown the ability to either directly or indirectly disrupt tumor cell infiltration, invasion, and proliferation (Sun et al. 2024b). For example, a recent study demonstrated that gold–silver core–shell hybrid nanomaterials significantly inhibit the migration and proliferation of adenocarcinoma cells that are promoted by fibroblasts, effectively limiting metastatic spread (Kovács et al. 2020). Another experiment found that ZnO@CuS nanoparticles enhance tumor cell sensitivity to photothermal therapy by generating free radicals, which suppress cell migration (Deng et al. 2021). Additionally, the conjugation of monoclonal antibodies with nanomaterials offers highly targeted therapy that spares healthy tissue, and the combination of multiple drugs with nanomaterials opens new avenues in cancer treatment (Jiang et al. 2020). Radiotherapy and chemotherapy remain pivotal cancer treatments, with nanomaterials enhancing their efficacy (Liu et al. 2018; Goel et al. 2023; Jackson et al. 2023). Gold nanocages, when coupled with radioactive isotopes, enhance the effects of radiotherapy by forming radiolabeled marker (Qin et al. 2017). Nanoscale radiosensitizers have been observed to improve tumor cell sensitivity to radiation, thereby amplifying radiotherapy outcomes (Jain et al. 2024). Furthermore, nanomedicines, which are designed to carry chemotherapeutic agents, can target specific receptors on tumor cells, leading to increased drug accumulation and enhanced chemotherapy effectiveness (Cun et al. 2019). Nanomaterials also address the challenge of tumor drug resistance. Some nanoliposomes can prolong drug circulation, increasing bioavailability (Gu et al. 2021), while nanomicelles bind with multidrug resistance-associated proteins to facilitate drug entry into tumor cells (Edis et al. 2021; Hu et al. 2020b). Cheng et al. demonstrated that pH-sensitive gold nanocage conjugates can release anticancer drugs in response to acidic conditions, enhancing both drug concentration in tumor tissues and radiotherapy effectiveness (Chen et al. 2023b). Interestingly, several studies have shown that nanoparticles can cross the blood–brain barrier and modulate the TME, enhancing the efficacy of drugs for neurological conditions (Liang et al. 2022; Xu et al. 2022). This potential application of nanomedicines in neurological diseases remains a promising area of future research (D’Aversa et al. 2024; Krsek et al. 2024). Further, the intrinsic properties of inorganic nanomaterials can be harnessed to disrupt the physical structure of the ECM, commonly reinforced by CAFs (Fu et al. 2022; Seo et al. 2021). For example, magnetically guided nanoparticles can be directed to fibrotic regions of tumors to deliver therapeutics that specifically disrupt CAF functions (Guo et al. 2024a). Finally, inorganic nanomaterials are not limited to therapeutic applications, some also possess diagnostic capabilities, such as fluorescence and magnetic resonance imaging (MRI) (Ren et al. 2024; Cheng et al. 2024b). Magnetic nanoparticles, particularly those based on iron oxide, are extensively used in magnetic MRI due to their superb contrast enhancement capabilities (Ferrera et al. 2024; Guedes et al. 2024). Their magnetic properties also allow for precise control and targeting when used with an external magnetic field, enhancing drug delivery efficiency to tumor sites, including those rich in CAFs (Hernández-Jiménez et al. 2022).

In conclusion, the application of nanomaterials in medicine continues to expand. However, while these materials offer significant promise, especially in cancer immunotherapy, there remain substantial challenges that must be addressed in future research.

Targeting cancer-associated fibroblasts with nanomaterials: therapeutic applications and mechanisms

Numerous previous studies have demonstrated that nanomaterials significantly affect CAFs (Li et al. 2018a), disrupting their functions and influencing the TME through various mechanisms (Wang et al. 2024d). On one hand, some nanomaterials serve as carriers for chemotherapeutic drugs or bioactive molecules, delivering them directly to CAFs (Huang et al. 2024a) and enhancing therapeutic efficacy while reducing off-target effects on healthy tissues (Geng et al. 2023). For instance, Li et al. developed reversibly bonded nanoparticles that can deliver anticancer drugs precisely to CAFs, illustrating their potential in targeted therapy (Yu et al. 2020). Additionally, Aljabali et al. highlighted that some nanomaterials possess immunomodulatory properties, facilitating the clearance or control of CAFs by modulating immune response (Aljabali et al. 2023).

Beyond drug delivery, specific nanomaterials directly target CAF-related molecular pathways to inhibit CAF activity (Zhou et al. 2021; Xin et al. 2021). For example, Zhou et al. developed a method using α-FAP-Z@FRT nanomaterials to target FAP on the surface of CAFs, this material selectively targets FAP expression in CAFs without affecting non-tumor tissues (Zhou et al. 2021). Moreover, different nanomaterials can affect CAFs in various ways. Further, gold-based nanomaterials, such as gold nanoparticles (GNPs) and gold nanocages, have demonstrated potential to modulate critical pathways within CAFs (Alhussan et al. 2022, 2021).For instance, Li et al. utilized a complex nanocomposite involving graphene oxide, gold nanoparticles, and fluorescent dyes, which was observed to release chemicals selectively to eliminate CAFs upon near-infrared laser irradiation (Yu et al. 2020). Additionally, certain nanomaterials function as carriers for photothermal therapy, generating heat upon exposure to light to induce apoptosis in CAFs (Li et al. 2018a). For instance, Mukherjee et al. demonstrated that 20 nm gold nanoparticles can transform CAFs into a quiescent state rich in lipids, inhibiting matrix deposition. Similarly, studies indicate that gold nanocages, nanoparticles, and nanorods can target and suppress CAF growth and function through photothermal effect (Hossen et al. 2019; Zheng et al. 2020). Specifically, gold nanocages disrupt CAF structures via photothermal therapy, impeding their proliferation and secretory function (Zheng et al. 2020), while gold nanoparticles selectively target CAFs to inhibit their proliferation and migration capabilities (Hossen et al. 2019). Nanomaterials offer unique capabilities for modulating key biochemical pathways within cancer-associated fibroblasts (Zhang et al. 2024b). Specific nanomaterials such as gold nanoparticles and liposomal formulations have been explored for their potential to interfere with TGF-β and IL-6 signaling pathways, pivotal in CAF-mediated tumor progression and immunosuppression (Pradhan et al. 2023; Zheng et al. 2023a). For instance, gold nanoparticles, when engineered to carry TGF-β inhibitors, target the fibrotic activity of CAFs (Yang et al. 2021; Zhang et al. 2021). By disrupting TGF-β signaling, these nanoparticles reduce the fibroblastic activation and ECM deposition, which are crucial for tumor stroma formation and immunosuppression. Liposomal carriers encapsulating IL-6 siRNA effectively reduce the expression of IL-6 in CAFs (Zhang et al. 2024c; Dana et al. 2022). This reduction dampens the JAK/STAT signaling pathway, thereby mitigating the inflammatory and tumor-promoting activities of CAFs (Fang et al. 2023; Ahrens et al. 2017). Interestingly, recent research has shown that some nanomaterials can paradoxically promote the growth and function of CAFs, stimulating their proliferation and migration (Chen et al. 2023b; Fei et al. 2023). These findings may provide a new perspective for targeted treatment of CAFs and cancer immunotherapy. Moreover, we discovered that certain nanomaterials enable the detection of gene expression and products in CAFs, which could facilitate studies on their role in tumor development in the future (Cun et al. 2019). While these innovative ideas currently lack practical applications, they hold promise for future research and clinical applications.

Nanomaterials as modulators of cancer-associated fibroblasts in the tumor microenvironment

Research on how nanomaterials interact with CAFs within the TME is a key area in modern cancer therapy (Zhang et al. 2023c; Bromma et al. 2020). Nanomaterials modulate cellular-level biological activities within the TME due to their unique size and surface properties (Hu et al. 2022). These materials influence the behavior of CAFs either through direct physical interactions or by releasing specific chemical signals that promote or inhibit their pro-tumorigenic functions (Kovács et al. 2020). For instance, some nanomaterials alter the ECM composition, impacting the support that CAFs provide to tumor cell (Liu et al. 2019a; D’Aversa et al. 2024). To be specific, incorporating ECM-degrading enzymes like hyaluronidase or collagenase into nanocarrier designs can help break down the fibrous barrier, improving the penetration and distribution of nanoparticles within the tumor stroma (Chandrasekar et al. 2024; Qiu et al. 2024).

Nanomaterials within the TME not only serve as carriers for drugs and bioactive molecules (Yu et al. 2020; Yao et al. 2020). For example, specific nanomaterials regulate the availability of oxygen and nutrients, promoting apoptosis in tumor cells and subsequently reducing tumor volume (Qin et al. 2017; Yuan et al. 2021; Ruan et al. 2022). Hypoxia, a common feature in solid tumors, significantly affects the biochemical environment, altering the reactivity of nanomaterials (Song et al. 2024; Li et al. 2025). This can lead to premature degradation or deactivation of therapeutic agents carried by the nanoparticles, or it may change the way these materials are taken up by CAFs and other tumor cells (Wang et al. 2020). For example, developing nanomaterials that are activated by or responsive to hypoxic conditions can turn this TME characteristic into an advantage, triggering drug release or activation specifically in low-oxygen zones, thus targeting CAFs more effectively (Zhang et al. 2019; Zu et al. 2023). Additionally, these nanomaterials can modulate the immune system by targeting and activating various immune cells, thereby bolstering the immune response and enhancing the effectiveness of cancer therapies (Han et al. 2020b; Fei et al. 2023). Furthermore, nanomaterials exhibit therapeutic potential by regulating the roles of CAFs in immune responses, angiogenesis, and tumor tissue stiffening (Lu et al. 2024; Li et al. 2018b). For instance, certain nanomaterials influence the physical and chemical dynamics of the TME. They disrupt angiogenesis in tumors and regulate the secretion of growth factors by tumor-associated fibroblasts, effectively inhibiting tumor growth and metastasis (Liang et al. 2022; Zhao and Rodriguez 2013).

Despite challenges such as targeting precision and potential off-target effects, current research focuses on enhancing nanomaterial design to overcome these issues (Kang and Li 2023). Overall, the interactions between nanomaterials and CAFs enrich our understanding of the complexity of the TME and open avenues 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.

Immunomodulatory roles of nanomaterials targeting CAFs

CAFs play a central role in maintaining an immunosuppressive TME by recruiting and modulating immune cells through cytokine and chemokine secretion (Chandrasekar et al. 2024). Nanomaterials, when designed to target CAFs specifically, have the potential to disrupt this immune suppression and reprogram the TME to favor anti-tumor immune responses (Wang et al. 2023a; Shen et al. 2023). Although the diversity of nanomaterials leads them to be able to control the tumor immune microenvironment in a state of "activation" or "inhibition" by directly targeting specific cellular or molecular mechanisms, many materials are currently designed to target CAFs cells, which inhibit tumor immunity (Jian et al. 2024; Zhen et al. 2017; Zang et al. 2022).

Nanoparticles that specifically target CAFs, such as those delivering FAP- or α-SMA-targeted therapies, can significantly alter cytokine profiles within the TME (Rodponthukwaji et al. 2024; Priwitaningrum et al. 2016). By downregulating immunosuppressive cytokines, these nanoparticles can alleviate T-cell suppression, enhance T-cell activation, and potentially improve T-cell infiltration into the tumor (Liu and Zhao 2024; Wang et al. 2024e). For instance, in the study by zhou et al., liposomal nanoparticles loaded with TGF-β inhibitors have shown promise in reprogramming the TME, reducing the immunosuppressive signals that prevent effective T-cell responses (Zhou et al. 2024a). By diminishing CAF-mediated suppression, nanoparticles can improve the efficacy of immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors (An et al. 2023; Gong et al. 2021). Studies have shown that when CAF-targeting nanoparticles are combined with PD-L1 inhibitors, there is an increase in T-cell infiltration and activation within tumors (An et al. 2023; Tan et al. 2021). For example, gold nanoparticles conjugated with immune-modulatory ligands have been observed to enhance PD-1 blockade efficacy in melanoma models by reducing CAF-derived T-cell suppression (Cao et al. 2021). Further, CAFs often recruit and polarize macrophages toward an immunosuppressive M2 phenotype (Perez-Penco et al. 2024; Wei et al. 2024), which supports tumor growth and immune evasion (Tomassetti et al. 2024). However, nanoparticles targeting CAFs can disrupt this process by altering the CAF-derived cytokine environment (Pradhan et al. 2023), leading to a shift from M2 (immunosuppressive) to M1 (pro-inflammatory, anti-tumor) macrophage phenotypes (Gong et al. 2024). For instance, polymeric nanoparticles delivering IL-6 inhibitors to CAFs have demonstrated the ability to reduce M2 macrophage recruitment, reprogramming the TME to support a more inflammatory and immune-activating environment (Feng et al. 2024).

In addition, combining CAF-targeting nanomaterials with immune checkpoint inhibitors, such as PD-1 or PD-L1 inhibitors, represents a promising therapeutic strategy (Liu et al. 2024b). CAF-targeting nanoparticles can “prime” the TME by reducing immune suppression, creating a more receptive environment for immune checkpoint inhibitors to work effectively (Table 3). Studies have shown that pre-treatment with CAF-targeting nanoparticles such as TGF-β inhibitor-loaded liposomes, can decrease CAF-derived immunosuppressive factors and enhance T-cell infiltration (Zhen et al. 2017; Wang et al. 2024f). When followed by PD-L1 inhibitors, these primed tumors respond better, with increased T-cell activation and tumor regression observed in preclinical models of melanoma and lung cancer (Ou et al. 2022; Zhang et al. 2023d). In some studies, nanoparticles targeting CAFs have also been paired with chimeric antigen receptor T-cell (CAR-T) therapy (Dharani et al. 2024). By disrupting CAF-mediated barriers and reducing the immunosuppressive cytokine environment, CAF-targeting nanoparticles have been shown to improve CAR-T cell infiltration and efficacy in solid tumors (Zhang et al. 2023e; Liu et al. 2023b).

Table 3 Summary of immunomodulatory effects and combination therapies

Tailoring nanomaterials to target CAF subtypes in cancer immunotherapy

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells that exhibit distinct phenotypes and functions depending on the tumor context. The primary CAF subtypes identified in various cancers include myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) (Caramelo et al. 2023; Melchionna et al. 2023). Each subtype contributes differently to tumor progression, ECM remodeling, and immune modulation (Schütz et al. 2023; Chen et al. 2024a; Vaish et al. 2021). Consequently, a “one-size-fits-all” approach to targeting CAFs is inadequate, instead, nanomaterials must be tailored to interact with specific CAF subtypes to achieve optimal therapeutic effects (Zhang et al. 2024d; Yamamoto et al. 2023).

. Therefore, integrating tumor-specific CAF targeting into nanomaterial design can enhance the precision and therapeutic efficacy of nanomedicine.

Targeting myCAFs

myCAFs are characterized by the expression of α-smooth muscle actin (α-SMA) and are primarily involved in ECM production and stiffening, creating a physical barrier that hinders drug penetration and immune cell infiltration (Kearney et al. 2024). This CAF subtype is particularly abundant in desmoplastic tumors such as pancreatic and breast cancers (Burley et al. 2022; Zeltz et al. 2019). To specifically target myCAFs, nanoparticles can be functionalized with ligands or antibodies against α-SMA or other ECM-associated proteins highly expressed by myCAFs (Yang et al. 2021; Priwitaningrum et al. 2016). For instance, nanoparticles conjugated with α-SMA-targeting peptides have shown promise in preclinical studies by accumulating selectively within myCAF-rich regions, reducing ECM density, and enhancing therapeutic penetration (Zheng et al. 2023b). In a preclinical study by Tista Roy Chaudhuri and his colleagues, a nanoparticle platform conjugated with α-SMA-targeting antibodies demonstrated selective accumulation in myCAF-dense areas within pancreatic tumors in mouse models (Roy Chaudhuri et al. 2016). This targeted approach reduced ECM stiffness, improved immune cell infiltration, and synergized with immune checkpoint inhibitors, suggesting a promising strategy for desmoplastic tumors.

Targeting iCAFs

iCAFs are characterized by high levels of FAP and the secretion of pro-inflammatory cytokines such as IL-6 and IL-8 (Yang et al. 2023b; Kearney et al. 2024), which promote an immunosuppressive environment by recruiting immunosuppressive cells and supporting cancer cell survival (Liu et al. 2024c; Thorlacius-Ussing et al. 2024; Morgan et al. 2023). iCAFs are prevalent in tumors with a strong inflammatory component, such as melanoma and certain gastrointestinal cancers (Ran and Chen 2024; Agorku et al. 2024; Picard et al. 2023). Nanoparticles can be modified with FAP-specific ligands, antibodies, or small-molecule inhibitors to target iCAFs selectively (Rodponthukwaji et al. 2024; Zhang et al. 2024e). FAP-targeted nanoparticles have been shown to reduce the immunosuppressive influence of iCAFs by delivering payloads that either silence cytokine production or modulate immune cell recruitment (Zhao et al. 2024). FAP-targeted liposomes loaded with IL-6 and IL-8 siRNAs were shown to reduce pro-inflammatory cytokine levels in melanoma mouse models (Aslan et al. 2024; Barati et al. 2022), thereby diminishing immunosuppressive signaling within the TME and enhancing the efficacy of T-cell-based therapies (Salotto et al. 2022). This approach highlights the therapeutic potential of targeting iCAFs in inflammatory tumor environments.

Targeting apCAFs

apCAFs possess the unique ability to present antigens via MHC-II molecules but generally lack co-stimulatory signals, resulting in anergy or tolerance of T cells within the TME (Kerdidani et al. 2022; Macy et al. 2023). Targeting apCAFs is challenging but potentially impactful, as modifying their interaction with immune cells could alter immune dynamics in favor of anti-tumor activity (No Author 2022; Macy et al. 2023). Nanoparticles designed to target MHC-II molecules or deliver agents that block inhibitory pathways within apCAFs could mitigate T-cell anergy (Srivastava et al. 2024; Liu et al. 2022b). For instance, nanomaterials conjugated with MHC-II blocking peptides or small molecules could reduce the suppressive effects of apCAFs on T-cell function, enabling more effective immune responses in tumors such as ovarian and gastric cancers where apCAFs are more prominent (Noureddine et al. 2023; Zheng et al. 2021). In ovarian cancer mouse models, MHC-II-targeted nanoparticles have been shown to interfere with apCAF-mediated T-cell anergy (Noureddine et al. 2023), thereby increasing T-cell activation and enhancing anti-tumor responses. Though in its early stages, this approach underscores the potential for highly specific targeting of CAF subtypes based on unique immune-modulatory properties.

Different tumor types in targeting strategies

The effectiveness of targeting strategies may vary significantly across different types of tumors (Table 4). For example, breast cancers with a high presence of iCAFs might benefit more from FAP-targeted therapies (Rodponthukwaji et al. 2024), while pancreatic cancers, characterized by dense stromal barriers predominantly formed by myCAFs, might be better addressed with α-SMA-targeted approaches (Ferraz et al. 2020; Roy Chaudhuri et al. 2016). Moreover, apCAFs play a notable role in ovarian cancer by inducing T-cell tolerance. Hence, MHC-II-targeted nanoparticles could be tailored to address T-cell anergy specifically in ovarian cancer models (Noureddine et al. 2023).

Table 4 Recent examples in CAF subtype-targeting nanomaterials

The role of CAF subtypes and their abundance can vary significantly between tumor types, necessitating tumor-specific targeting strategies (Huang et al. 2023, 2024b). However, by incorporating tumor-specific CAF targeting into nanomaterial design, we can enhance the precision of nanomedicine and improve therapeutic outcomes in a range of tumor microenvironments in the future.

Enhancing nanoscale drug delivery systems for targeting cancer-associated fibroblasts

Nanoscale drug delivery systems offer numerous advantages over traditional drug therapies (Wang et al. 2024b; Jia et al. 2021). However, challenges remain, particularly regarding their ability to effectively penetrate solid tumors, including proliferative connective tissue tumors (D’Aversa et al. 2024; Yunna et al. 2021). Therefore, it is essential to implement strategies that enhance the penetration and permeability of nanomedicines to improve drug delivery capabilities (Izci et al. 2022; Fang et al. 2020; Zhao et al. 2018). In this context, we present several enhanced delivery system approaches aimed at optimizing the targeting of CAFs within the TME (Fig. 3) Arranja et al. (2017).

Fig. 3

^© 2017 by the authors

A Nanomedicines and tumor targeting. Nanomedicines must overcome various barriers to achieve efficient tumor-targeted drug delivery. B Mechanisms of tumor targeting mediated by nanomedicine, passive, active, triggered. Reproduced from Arranja et al. (2017), Copyright

Cutting-edge gene delivery approaches for targeting CAFs and tumor cells

Traditionally, the study of DNA and RNA has been fundamental in biology. In one study, researchers developed a polymer known as 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 the inhibition of CAF proliferation and tumor growth (Zhang et al. 2023f). 5-Fluorouracil (5-FU), a DNA synthesis inhibitor, blocks the normal thymine nucleotide biosynthesis pathway, hindering the growth and division of tumor cells and CAFs; however, it also affects normal cells (Gong et al. 2023). In a study conducted by Handali and colleagues, a novel folate liposome was found to deliver fluorouracil more effectively to cancer cells while reducing toxicity (Handali et al. 2019). Similarly, Jain et al. discovered that a specific type of microRNA can enhance the sensitivity of colorectal cancer to radiotherapy by regulating tumor cell apoptosis and DNA damage repair pathways (Jain et al. 2024). In the research by Sheng et al., a CAF-targeted poly (lactic-co-glycolic acid) (PLGA) nanoemulsion was utilized to simultaneously deliver doxorubicin (DOX) and small interfering RNA (siRNA) targeting hepatocyte growth factor (HGF) for chemotherapy and gene therapy. Remarkably, the delivered siRNA reduced HGF expression in remaining CAFs, effectively overcoming chemotherapy-induced upregulation of HGF mRNA and preventing the increase of CAFs through an autocrine HGF feedback loop (Shen et al. 2023). These synergistic effects led to significant inhibition of tumor proliferation, migration, and invasion, as well as improved tumor permeability. In a nutshell, nanomaterials offer unique advantages when used in combination with traditional cancer therapies such as chemotherapy, radiotherapy, and immunotherapy (Guo et al. 2023; Hou et al. 2019; Truffi et al. 2019). By facilitating targeted delivery and controlled release of therapeutic agents, nanomaterials can enhance treatment efficacy while potentially reducing systemic toxicity (Andoh et al. 2024; You et al. 2018). Nanoparticles such as liposomes and polymeric nanoparticles have been successfully used to encapsulate chemotherapeutic agents like docetaxel and doxorubicin, enhancing drug accumulation in tumor tissues and minimizing exposure to healthy cells (Beheshtizadeh et al. 2024; Xu et al. 2024a). Clinical trials have demonstrated that such nanoparticle formulations can significantly reduce cardiac toxicity commonly associated with doxorubicin (Chen et al. 2024b). Admittedly, nanoparticles designed to deliver cytokines such as IL-2 or checkpoint inhibitors such as PD-L1 blockers directly to the tumor microenvironment have shown promise in preclinical models (Zhang et al. 2023g; Chao et al. 2024). These strategies help to activate and sustain immune responses locally, potentially overcoming the immunosuppressive TME and leading to better clinical outcomes.

Furthermore, siRNA, a type of small RNA, can inhibit gene expression by interfering with the stability and translation of targeted mRNA molecules. Numerous studies have demonstrated that siRNA can be encapsulated within liposomes to inhibit gene expression in tumor cell (Pei et al. 2019; Sohn 2020). However, there are only a few studies showing that siRNA may also act on CAFs to inhibit their biological functions (Suh et al. 2020; Hu et al. 2024b), indicating a need for further research in this area. Lastly, researchers have developed a dual-labeled nanoprobe based on small extracellular vesicles (sEVs) that can be used for tumor detection and diagnosis (Santos-Coquillat et al. 2022). This technology also has potential as a valuable tool for studying the biological behaviors of nanosystems in drug delivery, which we believe holds significant application value for future research.

Applications of small-molecule drugs and their carriers in targeting cancer-associated fibroblasts

Currently, numerous small-molecule drugs are utilized in cancer treatment and to improve TME (Liu et al. 2019a; Bromma et al. 2020). This highlights the advantages of small-molecule drugs in targeting CAFs and contributing to cancer immunotherapy. In this section, we summarize recent advancements in small molecule-loaded drug delivery systems designed to target CAFs.

Nanodrug carriers, such as Cellax-DTX nanoparticles, deliver chemotherapy drugs with high specificity to CAFs, promoting their apoptosis and modulating the TME (Ernsting et al. 2015). Furthermore, Sitia and colleagues developed functionalized H-ferritin nanocages combined with fragments of fibroblast activation protein (FAP) antibodies, creating highly specific drug carriers with strong affinity for CAFs (Sitia et al. 2021). Similarly, Duan designed a dual-targeted liposome-hybrid micelle system (RPM@NLQ) triggered by matrix metalloproteinase (MMP), which sequentially delivers quercetin (Que) and paclitaxel (PTX) to CAFs. This system downregulates Wnt16 expression in CAFs, thus enhancing fibrosis reduction (Duan et al. 2022). Additionally, a specialized nanoemulsion (NE) system has been developed to deliver the anti-fibrotic drug fraxinellone (Frax) to CAFs (Santos-Coquillat et al. 2022). Researchers observed that Frax NE, when combined with tumor-specific peptide vaccines, may represent an effective and safe treatment strategy (Santos-Coquillat et al. 2022). Other small-molecule compounds, such as superparamagnetic iron oxide nanoparticles (SPIONs), target fibroblast growth factor 2 (FGF2) precursors in CAFs, inhibiting their production and enhancing the efficacy of gemcitabine (Mardhian et al. 2020).

Clara et al. demonstrated that hydrogen peroxide plays a crucial role in the interaction between gold–iron alloy nanoparticles and CAFs (Faria et al. 2023). Additionally, some macromolecular systems, such as the nano-composite hydrogel developed by Liu et al., and the peptide–doxorubicin (GFLG–DOX) conjugate of polyamidoamine (PAMAM) dendritic macromolecules designed by Rashed M et al., have shown the potential to improve chemotherapy drug penetration and efficacy without harming healthy tissues (Liu et al. 2019c; Almuqbil et al. 2020).

Innovative strategies for targeting cancer-associated fibroblasts in immunotherapy

Targeting CAFs has emerged as a critical strategy in cancer immunotherapy. Recent advances have led to the development of antibodies and other ligands that specifically bind to receptors on the surface of CAFs, inducing their apoptosis or inhibiting their proliferation. For instance, Liang et al. developed a peptide-assembled nanosystem that effectively inhibits CAF metastasis and prostate cancer progression (Lang et al. 2019). Additionally, strategies to reprogram CAFs are being explored. One such approach involves metabolic reprogramming, where the regulation of glucose uptake and lactate production forms the basis for new drug-targeting strategies (Li et al. 2021b; Becker et al. 2020). For example, Theivendran et al. utilized DMON-P to reprogram CAFs, downregulating CAF-specific biomarkers and successfully delivering doxorubicin (Dox) to inhibit tumor growth (Theivendran et al. 2024). Furthermore, DNA-targeted vaccines show great promise in CAF-targeted immunotherapy (Geng et al. 2019). Geng et al. developed a vaccine targeting both fibroblast activation protein alpha (FAPα) and the tumor antigen survivin, which not only eliminated CAFs, but also regulated the tumor microenvironment, thereby enhancing T-cell-mediated anticancer effect (Geng et al. 2020). Another notable study by Hu and colleagues involved the use of CAFs as antigens to create vaccines that stimulated an immune response specifically targeting CAFs. Their experiments showed success in both in vitro and in vivo models, demonstrating the feasibility of using CAFs as vaccine antigens in cancer therapy, a concept that warrants further exploration (Hu et al. 2024b). Moreover, activated T-cell therapies are also gaining attention. One study introduced activated T cells into the tumor site, where they specifically targeted CAFs, leading to reduced tumor growth (Pei et al. 2019). Liposomes serve as effective carriers for CAF-targeted therapies as well. For instance, Li et al. conjugated single-chain variable fragment (scFv) antibodies to liposomes, utilizing the high-affinity binding of monoclonal antibodies to enhance the penetration of liposomes into tumor tissues, thereby improving the efficacy of colorectal cancer treatment (Li et al. 2021c). Furthermore, a novel co-loaded liposome targeting the insulin receptor (IR) was shown to reduce CAF activity, thus inhibiting tumor progression (Sun et al. 2024c). In another study, Lee et al. used the anti-fibrotic drug nintedanib to decrease CAF activation and proliferation. Nintedanib was found to block the platelet-derived growth factor receptor beta (PDGFRβ) signaling pathway, reducing the secretion of interleukin-6 (IL-6) and thereby inhibiting CAF function (Lee 2023).

Nanomaterials in clinical trials

While preclinical studies have demonstrated the promise of nanomaterials in targeting CAFs and modulating the TME, translating these findings into clinical practice presents significant challenges. Here, we review the current status of nanomaterial-based therapies in clinical trials and discuss specific nanomaterials that have progressed to advanced preclinical or clinical trial phases, as well as the challenges they face in clinical translation (Table 5). Gold nanoparticles, for instance, have been tested in Phase I/II trials for their efficacy in targeting tumor microenvironments without adverse systemic effects (Sun et al. 2024d; Dai et al. 2018). Liposome-based therapies have also reached clinical trials, showcasing potential in targeted drug delivery to reduce tumor resistance (Li et al. 2024e; Zhang et al. 2024g). Liposomal formulations, such as Doxil (doxorubicin encapsulated in liposomes), have already been approved for cancer therapy and have inspired further development of liposome-based therapies in cancer immunotherapy (Xu et al. 2024b). Liposomes can encapsulate immunotherapeutics and target them to specific cells within the TME, improving treatment specificity and reducing systemic toxicity (Chen et al. 2016). Poly (lactic-co-glycolic acid) (PLGA) nanoparticles are widely used in drug delivery due to their biocompatibility and ability to encapsulate both hydrophobic and hydrophilic drugs (Shen et al. 2023; Ye et al. 2020). Clinical trials are ongoing to assess the efficacy of PLGA nanoparticles in delivering checkpoint inhibitors directly to tumors, which could increase immune activation within the TME.

Table 5 Key nanomaterial-based therapies currently in clinical trials

One of the primary challenges in nanomedicine is ensuring biocompatibility and minimizing toxicity (Chandrasekar et al. 2024; Damani et al. 2024; Xu et al. 2024c). For instance, while liposomes and PLGA nanoparticles have generally favorable biocompatibility profiles (Mirza-Aghazadeh-Attari et al. 2022; Ali et al. 2021), other nanomaterials, such as metal nanoparticles, can induce oxidative stress or accumulate in organs, posing risks of long-term toxicity (Kahil et al. 2024; Liang et al. 2024b). In addition, efficiently delivering nanomaterials to CAFs and other TME components remains difficult (Zheng et al. 2023a). The dense ECM created by CAFs can act as a physical barrier, limiting the penetration of nanoparticles into tumor tissues (Zhang et al. 2024f; Ye et al. 2024). Techniques like size optimization and ligand-mediated targeting are being explored to improve intratumoral delivery and CAF specificity (Singh et al. 2024a; Kaps and Schuppan 2020). However, advancements in nanotechnology and regulatory science are expected to address these hurdles, enhancing the translational pathway for nanomaterials in cancer therapy (Luo et al. 2024; Guo et al. 2024b; Chen et al. 2024c). Continued collaboration between researchers, clinicians, and regulatory bodies is crucial to harness the full potential of nanomedicine.

Conclusion and future perspectives research

The past decades has consistently highlighted the multifaceted role of CAFs in tumor development and progression. CAFs not only contribute to the formation of the ECM that constitutes the tumor stroma, but also secrete growth factors, chemokines, exosomes, and metabolites that influence virtually all aspects of tumor biology, including drug resistance and treatment responses (Rizzolio et al. 2022). As scientific understanding of CAFs deepens, novel avenues for targeted immunotherapy based on their unique properties are emerging. A growing body of evidence suggests a significant correlation between programmed death-ligand 1 (PD-L1) expression levels and the degree of CAF infiltration in tumors. Certain CAF subsets have been shown to suppress T-cell activity by secreting PD-L1, thereby aiding tumor cells in evading immune detection and destruction (Yin et al. 2023; Choueiri et al. 2021; Gorchs et al. 2020). This highlights the importance of further research into the interplay between PD-L1 and CAFs to unravel the regulatory mechanisms underlying the tumor immune microenvironment. Understanding these mechanisms will be pivotal for developing more effective immunotherapies that can enhance the body's ability to combat tumors. Moreover, CAFs exert a direct influence on tumor cell behavior and characteristics through the secretion of growth factors, the activation of protein receptor signaling pathways, and the modulation of gene expression. Targeting these critical pathways may offer a promising strategy for combating cancer. Here, we summarize key drugs and therapies currently under investigation or in clinical use that aim to inhibit the pro-tumorigenic functions of CAFs (Table 6).

Table 6 Key targets and therapeutic strategies involving CAFs

Table 6 provides a comprehensive overview of key targets and therapeutic strategies involving CAFs, highlighting innovative approaches in cancer immunotherapy. It enumerates targets like PD-L1, TGF-β, and IGF-1 critical in modulating CAF activity within the tumor microenvironment. Innovative strategies include monoclonal antibodies such as adebrelimab targeting PD-L1 to enhance T-cell-mediated immune responses, and inhibitors like galunisertib aimed at suppressing CAF activation by inhibiting TGF-β. Small-molecule inhibitors and therapeutic antibodies explore potential in attenuating CAF-induced tumor activities, suggesting novel avenues for precision medicine in diverse cancer treatments. These strategies underscore the importance of targeting CAFs to disrupt their pro-tumorigenic functions and enhance therapeutic outcomes.

While nanomaterials can modulate immune responses and enhance drug delivery, their interaction within the complex TME requires a deeper understanding to avoid unintended immunosuppressive effects (D’Aversa et al. 2024; Chen et al. 2016; Mardhian et al. 2018; Avgoustakis and Angelopoulou 2024). Moreover, the safety of nanomaterials—particularly in terms of biodegradability and long-term toxicity—remains a major concern, necessitating rigorous clinical validation (Yuan et al. 2023; Mu et al. 2021; Kesharwani et al. 2024). The prolonged presence of nanoparticles in the body may lead to unforeseen complications, requiring careful management of these risks (Mardhian et al. 2018; Zhang et al. 2024h; Lee et al. 2024). Despite these challenges, nanomaterials offer revolutionary potential in cancer therapy (Dasgupta et al. 2023). Future research should focus on overcoming these limitations through the development of more specific, efficient, and biocompatible nanomaterials (Zheng et al. 2022; Zhang et al. 2022b; Affinito et al. 2024; Tan et al. 2022). This includes improving delivery systems, exploring combination therapies, and enhancing our understanding of the TME (Sung and Lee 2024; Tang et al. 2021; Mu et al. 2024; Choi et al. 2024). A promising avenue involves the development of dual-functional nanomaterials that target both CAFs and immune checkpoints, which could reactivate the immune system while disrupting the supportive TME (Geng et al. 2023; Liu et al. 2024b). 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 (Zheng et al. 2023a; Zhang et al. 2020b) However, due to limited current research, there is not sufficient data to extensively discuss this system.

Scaling up the production of nanomaterials while maintaining stringent quality and safety standards remains a critical challenge in advancing them from the laboratory to clinical settings (Pednekar et al. 2024). Regulatory approval processes are also complex due to the novel properties of nanomaterials, requiring tailored assessment protocols (Singh et al. 2024a, 2024b; Tagaras et al. 2024). Precision engineering of nanomaterials and advanced targeted delivery systems could help address these challenges (Kesharwani et al. 2024; Liu et al. 2024d; Zheng et al. 2024). Moreover, developing combination therapies that incorporate nanomaterials may maximize therapeutic efficacy while minimizing side effects by enabling lower dosages and more targeted action (Chen et al. 2024d; Zare et al. 2024; Overchuk et al. 2023).

To overcome these hurdles, interdisciplinary collaboration between researchers, clinicians, and regulatory bodies will be crucial (Han and Santos 2024; Cheng et al. 2024c). Integrating emerging technologies such as machine learning for predictive modeling of nanomaterial interactions within the TME could accelerate the development of effective therapies (Gao et al. 2024; Leong et al. 2021). Additionally, artificial intelligence (AI) could revolutionize nanomaterial design by optimizing nanoparticle properties for enhanced delivery and efficacy based on vast datasets that identify biomarkers (Gao et al. 2024; Bag et al. 2024; Mahajan and Bhattacharya 2024). In parallel, green nanomaterials, designed with sustainability in mind, offer an eco-conscious alternative for cancer treatment (Zhou et al. 2024b; Yang et al. 2023c). These materials utilize biodegradable components that pose minimal risk to the environment and human health (Montazersaheb et al. 2024; Balčiūnaitienė et al. 2022). Their biocompatibility and reduced toxicity make them ideal candidates for long-term therapeutic applications, contributing to both patient outcomes and global sustainability goals (Naseer et al. 2022; Zhong et al. 2021; Zhang and Ge 2020).