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All issues Volume 6 (2025) Vis Cancer Med, 6 (2025) 4 Full HTML
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Vis Cancer Med
Volume 6, 2025
Article Number 4
Number of page(s) 6
DOI https://doi.org/10.1051/vcm/2025005
Published online 17 March 2025

© The Authors, published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in the tumor microenvironment (TME) [1–3], playing crucial roles in cancer progression, including proliferation, invasion, and metastasis. CAFs represent a highly heterogeneous population, and extensive research has focused on identifying distinct subtypes and understanding their influence on tumor biology. Transcriptome sequencing analysis has revealed several CAF subtypes in cancers, such as pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BRCA). These include myofibroblastic cancer-associated fibroblasts (myCAFs), inflammatory/growth factor-rich CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) [4]. A study by Costa et al. identified four distinct CAF subgroups (CAF-S1 to CAF-S4), with two subtypes – CAF-S1 and CAF-S4 – exhibiting myofibroblastic characteristics and distinct functional roles in triple-negative breast cancer (TNBC). CAF-S1 fosters an immunosuppressive environment by secreting CXCL12, which attracts CD4+CD25+ regulatory T cells, while CAF-S4 appears to play a contrasting role [5].

MyCAFs are a significant subpopulation within CAF subtypes, exhibiting complexity and multifunctionality within the TME. However, the precise molecular mechanisms and signaling pathways by which myCAFs regulate tumor progression are still not fully understood. Moreover, translating these findings into clinical practice and developing therapeutic strategies targeting myCAFs remain significant challenges.

Immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapy, and tumor vaccines, has revolutionized cancer treatment by enhancing immune recognition and promoting immune cell infiltration to eliminate cancer cells. While immunotherapy has been effective in various cancers such as lung, breast, liver, gastrointestinal cancers, and melanoma, its efficacy is inconsistent across patients [6]. Immune evasion cells and the establishment of an immunosuppressive TME are major contributors to resistance against these therapies.

In this perspective, we review recent advances in understanding the role of myCAFs within the TME, particularly their involvement in creating an immunosuppressive milieu. We also explore the potential for targeting myCAFs in combination with immunotherapy as a novel therapeutic approach in the future.

The heterogeneity of CAFs

In the breast cancer microenvironment, CAFs exhibit high heterogeneity, primarily categorized into myCAFs, iCAFs, and apCAFs (Figure 1). MyCAFs exhibit elevated expression of markers such as α-smooth muscle actin (α-SMA), hyaluronan synthase 2 (HAS2), and type I collagen (COL I) [7]. They are typically distributed adjacent to cancer cells in clusters [8] and are capable of remodeling the extracellular matrix, promoting tumor invasion and metastasis. myCAFs can induce an immunosuppressive microenvironment by secreting extracellular matrix components and polarizing immune cells, such as TREM2+ macrophages [9]. Additionally, their elevated expression of components like type I collagen can lead to tumor fibrosis [10]. Transforming growth factor beta (TGF-β) is predicted to drive the formation of the myCAF lineage, whereas the IL-1-induced NF-κB signaling pathway is predicted to be responsible for the formation of the iCAF lineage [11]. ICAFs secrete a variety of pro-inflammatory cytokines, such as IL-6, IL-8, and leukemia inhibitory factor (LIF), which can regulate inflammatory responses in the TME [12]. ICAFs are typically found near blood vessels, suggesting a potential role in angiogenesis or vessel-related functions [8]. ICAFs are known subpopulations that respond well to immunotherapy. Studies have found that in “hot tumors”, iCAFs primarily facilitate the infiltration of immune cells into solid tumors through the CXCL12-CXCR4 axis [13]. ApCAFs are capable of activating CD4+ T cells through the expression of MHC II molecules and the CD74 invariant chain. However, due to their lack of classical co-stimulatory molecules such as CD80, CD86, and CD40, they cannot function as professional antigen-presenting cells. Their distribution within the TME is relatively dispersed [11]. ApCAFs can induce the formation and expansion of regulatory T cells (Tregs) in an antigen-dependent manner, thereby inhibiting the proliferation of CD8+ T cells and exerting an immunosuppressive effect. The formation of apCAFs may involve the NF-κB and TGF-β signaling pathways [12].

thumbnail Figure 1

The heterogeneity of CAFs. The CAFs in breast cancer TME are mainly classified into myCAF, iCAF, and apCAF based on their heterogeneity. MyCAFs exhibit elevated expression of α-SMA, HAS2, and COL I, typically distributed in clusters. ICAFs exhibit elevated expression of IL-6, IL-8, and LIF, typically distributed near blood vessels. ApCAFs exhibit elevated expression of MHC II molecules and CD74, distributed in a scattered pattern. MyCAF promotes tumor invasion and metastasis by remodeling the ECM, while iCAF regulates immune responses in TME and facilitates the infiltration of immune cells. ApCAFs modulate the immunosuppressive microenvironment in an antigen-dependent manner. MyCAF, myofibroblastic cancer-associated fibroblast; apCAF, antigen-presenting cancer-associated fibroblast; iCAF, inflammatory/growth factor-rich cancer-associated fibroblast; α-SMA, α-smooth muscle actin; HAS2, hyaluronan synthase 2; COL I, type I collagen; IL-6, interleukin-6; IL-8, interleukin-8; LIF, leukemia inhibitory factor; MHC Ⅱ, class Ⅱ major histocompatibility complex; CD74, CD74 molecule.

MyCAFs promote tumor progression and are associated with an immunosuppressive microenvironment

MyCAFs play a pivotal role in tumor progression across various cancer types through complex mechanisms. For instance, Hanley et al. found that elongated collagen fibers – associated with poor prognosis in cancers such as breast, esophageal, head and neck, and colorectal cancer – are uniquely regulated by α-SMA+ myCAFs [14]. These myCAFs are responsible for collagen fiber elongation, which contributes to adverse outcomes in multiple cancers. In the liver, fibrosis-associated myCAFs are similarly linked to the development of liver cancer. These myCAFs promote the malignant transformation of hepatocytes through several mechanisms [15], including, (1) interacting with immune cells and vascular endothelial cells to evade immune surveillance and form an immunosuppressive TME or increase angiogenesis; (2) enhancing stromal stiffness via activation of the ERK, PKB/Akt, and STAT3 signaling pathways, promoting cancer cell proliferation, invasion, and therapy resistance; and (3) secreting cytokines such as TGF-β, IL-6, IFNγ, and IL-4 to drive cancer cell growth. These findings demonstrate that myCAFs are key players in remodeling the TME and driving cancer progression through multiple pathways.

In addition to TME remodeling, myCAFs promote tumor invasion and metastasis by activating intracellular signaling pathways. TGF-β is a key driver of the transition of CAFs to the myCAF subtype. Research by Mucciolo et al. revealed that TGF-β induces autocrine activation of the EGFR/ERBB2 signaling pathway in myCAFs through amphiregulin, which in turn promotes PDAC metastasis in mice [16]. The EGFR activation in myCAFs may also be relevant to other cancer types [17]. These findings highlight the functional heterogeneity of CAFs and suggest that targeting myCAFs could provide novel therapeutic strategies for inhibiting metastasis.

In clear cell renal cell carcinoma (ccRCC), studies have found a significant correlation between myCAF enrichment and mesenchymal-like tumor cells, which are associated with primary resistance to ICIs therapy. This association is linked to a higher risk of metastasis, recurrence, and decreased overall survival, indicating that myCAFs may play a role in epithelial-mesenchymal transition (EMT) and ICIs resistance [18]. Combining myCAF-targeted therapies with immunotherapy may effectively counteract treatment resistance and prolong disease-free survival (DFS) in patients.

Although numerous studies indicate that myCAFs possess the ability to inhibit CD8+ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocytes (CTLs) against cancer cells, several specific subtypes of CAFs have a positive impact on the tumor immune microenvironment [19]. For example, elevated expression of FAP and PDGFRb in CAFs is associated with increased infiltration of CD8+ T cells in oropharyngeal squamous cell carcinoma [20]. The PLA2G2A+ CAFs subtype, which is enriched in HER2+ breast cancer patients, can also promote T cell infiltration within the TME [21].

While numerous studies have demonstrated the role of myCAFs in promoting tumor progression, the specific mechanisms through which they function are still not fully understood. Future research should focus on several key areas: (1) a more detailed investigation of the molecular mechanisms by which myCAFs promote tumorigenesis, particularly the role of specific signaling pathways; (2) the development and validation of therapeutic strategies targeting myCAFs to improve patient outcomes; and (3) the integration of multidisciplinary approaches, such as bioinformatics and clinical trials, to accelerate the translation of basic research findings into clinical applications.

Targeting MyCAFs combined with immunotherapy as a potential tumor therapeutic strategy

The growing recognition of CAFs as crucial regulators in the TME has led to an increasing focus on the role of myCAFs in promoting cancer progression and impacting patient survival. MyCAFs regulate cancer progression, including their role in matrix remodeling, angiogenesis, and immune modulation [22, 23]. As the most abundant component, myCAFs play a pivotal role in regulating the biological processes of tumor cells and other stromal cells through cell-cell contact, thereby rendering myCAFs of immense significance [24]. Recently, Bonneaud et al. [25] demonstrated that inhibiting MCL-1, a key regulator of mitochondrial integrity, can reverse the myofibroblastic phenotype and its pro-invasive properties in breast cancer, providing a promising avenue for stromal-targeted therapies. Similarly, NOX4, a subunit of the NADPH oxidase complex involved in reactive oxygen species (ROS) production, has been shown to correlate with myCAFs accumulation and poor patient outcomes [26]. Inhibiting NOX4 reduces myCAFs presence in the TME and slows tumor growth, further supporting the potential of targeting myCAFs across various cancers.

However, antitumor treatment targeting myCAFs still faces numerous clinical translation hurdles and potential off-target effects. MyCAFs promote tumor progression through the remodeling of extracellular matrix and the secretion of cytokines. The functional complexity and cellular heterogeneity necessitate a higher degree of precision in targeting strategies for myCAFs. In clinical translation research, the lack of unique biomarkers capable of specifically targeting myCAFs makes it difficult to ensure the accuracy of drug delivery systems [27]. Many drugs targeting myCAFs have shown promising results in animal models but have failed to achieve expected outcomes in clinical trials. For instance, the small molecule IPI-926, which inhibits myCAFs proliferation, did not succeed in clinical trials [28]. As mentioned above EGFR-activated myCAFs promote metastasis in pancreatic cancer, yet EGFR inhibitors may have differential effects on different CAF subtypes in clinical trials. The EGFR inhibitor neratinib reduced the number of myCAFs in mouse models but increased the number of iCAFs, suggesting potential off-target effects of myCAF-targeted therapy [16]. Additionally, myCAF-targeted therapy may also impact immune cell function. For example, targeting PWAR6 may affect NK cell function by altering glutamine availability [10]. Therefore, further research is needed to overcome the challenges and difficulties in myCAF-targeted therapy and clinical translation.

Immunotherapy, a breakthrough in cancer treatment, faces challenges such as resistance and varying patient responses. The correlation between myCAFs, immunosuppressive TME, and immunotherapy resistance has become a critical area of research. Tumors rich in myCAFs are often characterized by low cytotoxic T-cell infiltration, leading to resistance to ICIs. The combination of myCAF-targeted therapy and immunotherapy demonstrates different effects on various types of cancer [29, 30]. Notably, myCAFs exhibit activated ATM signaling pathways, which increase oxidative stress and DNA damage via NOX4. Inhibiting ATM significantly reduces myCAFs numbers and enhances CD8+ T cell infiltration into tumors, thereby improving the response to immunotherapy [31]. Furthermore, in breast cancer, myCAFs linked to extracellular matrix and TGF-β signaling pathways upregulate PD-1 and CTLA4 expression in Tregs, leading to primary resistance to immunotherapy [32]. The combined application of NOX4 inhibitors and immunotherapy has achieved partial progress in clinical trials. Based on interim data from the Phase 2 clinical trial (NCT05323656, https://clinicaltrials.gov/study/NCT05323656?id=NCT05323656&rank=1), the combination of Setanaxib (a NOX4 inhibitor) and Pembrolizumab (Keytruda) demonstrated good progression-free survival (PFS) in the treatment of patients with squamous cell carcinoma of head and neck (HNSCC).

Beyond mediating immunotherapy resistance, myCAFs are also implicated in resistance to HER2-targeted therapies, as well as tumor recurrence and metastasis in breast cancer [33]. These findings indicate the functional diversity of myCAFs, underscoring the need for further research into the molecular mechanisms governing their role in therapy resistance. Similar associations between myCAFs and immunosuppressive TME have been observed in other cancers, including PDAC, cervical squamous cell carcinoma (CSCC), oral squamous cell carcinoma (OSCC), and melanoma [34–37]. These observations collectively suggest that targeting myCAFs, in combination with ICIs, holds promise as a strategy to overcome immunotherapy resistance.

In addition to directly targeting myCAFs, inhibiting their differentiation and transformation may offer another avenue to suppress tumor progression. For example, in non-small cell lung cancer (NSCLC), tumor-associated macrophages (TAMs) give rise to myCAFs through the macrophage-myofibroblast transition (MMT) process. Targeting Smad3, a key gene regulating myCAFs differentiation, significantly reduced myCAFs numbers and delayed tumor growth [38]. Likewise, the transcription factor PRRX1 has been identified as a master regulator of the fibroblast-to-myofibroblast transition, suggesting that inhibiting PRRX1-mediated TGF-β signaling could effectively hinder myCAFs formation [39].

In summary, the complex interplay between myCAFs and other components of the TME, particularly immune cells, offers significant potential for therapeutic interventions. By reviewing recent research, it becomes evident that targeting myCAFs or inhibiting their differentiation, in combination with immunotherapy, may represent a promising direction for future cancer therapies. This combined approach could help overcome resistance to treatment and improve clinical outcomes, making it a key focus of ongoing and future research.

Conclusion and Future Prospects

The heterogeneity and functional diversity of CAFs, particularly the myCAFs subset, play pivotal roles in tumor progression and determining tumor outcomes. MyCAFs have gained significant attention for their critical involvement in tumor growth, stromal remodeling, and resistance to therapies, including immunotherapy. Tumors enriched with myCAFs are strongly associated with reduced patient survival, as well as increased tumor invasion and metastasis. Moreover, in several cancer types, myCAFs contribute to the formation of an immunosuppressive TME, further complicating treatment outcomes. As a result, combining immunotherapy with strategies that target myCAFs or inhibit their formation presents a promising therapeutic approach for overcoming treatment resistance and improving patient outcomes in the future.

Specifically, myCAF-targeted therapy can be combined with ICIs (such as PD-1/PD-L1 inhibitors) to enhance the tumor immune microenvironment. In addition, the combined application of myCAF-targeted therapy with traditional chemotherapy or radiotherapy may also benefit patients. For instance, in the case of TSPAN8+ myCAFs, a combination regimen of anti-TSPAN8 antibodies and SIRT6 activator MDL-800 can overcome chemotherapy resistance [7]. Since CAFs play a crucial role in tumor fibrosis and extracellular matrix remodeling, which may impact the efficacy of radiotherapy, targeting myCAFs can improve tumor radiosensitivity and enhance the therapeutic effect of radiotherapy [40]. In future research, multi-omics analyses such as single-cell RNA transcriptome and proteome, along with genetically engineered mouse models, can be utilized to delve deeper into the functions and molecular mechanisms of myCAFs, identify specific markers for myCAFs, and develop more precise targeted therapeutic strategies. Similarly, in clinical trials, further assessment in conjunction with CAF markers is needed to determine the efficacy and safety of targeting myCAFs.

Funding

This work was supported by the National Key R&D Program of China (2022YFA1105200), National Natural Science Foundation of China (82273337, 81972598).

Conflicts of interest

The authors declare no conflict of interest.

Data availability statement

This article has no associated data generated.

Author contribution statement

Conceptualization, W.D., Z.C.; Writing-original draft, W.D.; Writing-reviewing and editing, W.D., Z.C.

Ethics approval

Ethical approval was not required.

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Cite this article as: Wang D & Chen Z. Targeting myofibroblastic cancer-associated fibroblasts (myCAFs): a promising strategy for overcoming tumor progression and immunotherapy resistance. Visualized Cancer Medicine. 2025; 6, 4. https://doi.org/10.1051/vcm/2025005.

All Figures

thumbnail Figure 1

The heterogeneity of CAFs. The CAFs in breast cancer TME are mainly classified into myCAF, iCAF, and apCAF based on their heterogeneity. MyCAFs exhibit elevated expression of α-SMA, HAS2, and COL I, typically distributed in clusters. ICAFs exhibit elevated expression of IL-6, IL-8, and LIF, typically distributed near blood vessels. ApCAFs exhibit elevated expression of MHC II molecules and CD74, distributed in a scattered pattern. MyCAF promotes tumor invasion and metastasis by remodeling the ECM, while iCAF regulates immune responses in TME and facilitates the infiltration of immune cells. ApCAFs modulate the immunosuppressive microenvironment in an antigen-dependent manner. MyCAF, myofibroblastic cancer-associated fibroblast; apCAF, antigen-presenting cancer-associated fibroblast; iCAF, inflammatory/growth factor-rich cancer-associated fibroblast; α-SMA, α-smooth muscle actin; HAS2, hyaluronan synthase 2; COL I, type I collagen; IL-6, interleukin-6; IL-8, interleukin-8; LIF, leukemia inhibitory factor; MHC Ⅱ, class Ⅱ major histocompatibility complex; CD74, CD74 molecule.
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