A Promising Cancer Therapy Strategy: Targeting Signaling Pathways Involved in Cancer-Associated Fibroblast Phenotypic Modulation

Abstract

Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the tumor microenvironment, have attracted increasing attention because of their critical roles in tumor progression and their therapeutic potential. However, owing to the marked heterogeneity of CAFs, distinct CAF subtypes may exert divergent or even opposing functions. Consequently, indiscriminate depletion of CAFs may inadvertently eliminate tumor-restraining subtypes and thereby accelerate tumor progression. In contrast, selectively inhibiting the formation of tumor-promoting CAF subtypes or reprogramming CAFs toward quiescent or tumor-restraining phenotypes is considered a more promising therapeutic strategy. CAF phenotypic modulation is regulated by complex signaling networks, and comprehensive investigation of the underlying pathways may provide novel mechanistic insights and potential therapeutic candidates for CAF-targeted therapy. This review summarizes recent advances in signaling pathways involved in CAF phenotypic modulation and the corresponding targeted agents, with the aim of systematically elucidating CAF phenotypic plasticity and providing new perspectives for future drug development.

Graphical abstract

Keywords

cancer-associated fibroblasts / heterogeneity / phenotypic plasticity / signaling pathways / CAF-targeted therapy

Introduction

Cancer-associated fibroblasts (CAFs) are specialized fibroblasts found within tumor tissue and serve as the most crucial stromal cells in the tumor microenvironment. They are characterized by an elongated spindle shape, lacking epithelial, endothelial, and immune cell markers, and do not carry the mutations typically found in cancer cells^[1,2].

CAFs primarily function to provide physical support and remodel the tumor microenvironment^[3,4]. They modulate the extracellular matrix (ECM) by regulating the synthesis and degradation of matrix proteins^[1]. Through direct cell-to-cell contact and paracrine signaling, CAFs interact with tumor cells, immune cells, endothelial cells, and other stromal components within the tumor tissue^[1,2]. These interactions influence various tumor survival mechanisms, including growth, metastasis, immune evasion, angiogenesis, and drug resistance^[3,4].

Research on CAF classification has revealed significant phenotypic heterogeneity among CAFs derived from different solid tumors^[5,6]. Different tumor environments, fibroblast origins, and activating signaling pathways contribute to the formation of various CAF subtypes^[1,3]. Some subtypes promote tumor progression, while others exert tumor-restraining effects^[7,8]. Despite the strong correlation between CAFs and tumor prognosis confirmed in clinical studies^[9,10], this heterogeneity complicates targeted depletion approaches, which may inadvertently reduce tumor-restraining subtypes and lead to suboptimal outcomes or even accelerated tumor progression^[11]. Given the stemness exhibited by CAFs, reversing their differentiation or converting them into non-tumor-promoting phenotypes represents a promising therapeutic strategy^[12]. This review synthesizes the activators and signaling pathways associated with CAF phenotypes, integrates these findings with current advances in pathway-targeting drug development, and aims to offer new insights for future CAF-targeted therapeutic strategies.

Key signaling pathway of CAF phenotypic modulation

JAK/STAT3 signaling pathway

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway is a signaling cascade activated by the non-receptor tyrosine kinase JAK, which drives the phosphorylation of STAT3^[13].

In CAFs, the JAK/STAT3 pathway is primarily activated by interleukin-6 (IL-6)-like cytokines, including IL-6, leukemia inhibitory factor (LIF), and interleukin-11 (IL-11). In colon cancer, CAFs stimulated by IL-6 or IL-11 exhibit cancer-promoting effects by enhancing angiogenesis^[14]. In breast cancer, prostate cancer, and cutaneous squamous cell carcinoma (SCC), IL-6 and LIF drive the development of CAF subtypes that promote tumor invasion and migration through matrix remodeling^[14–16]. Notably, CAF subtypes induced by IL-6 in breast cancer tissue overexpress transforming growth factor-β (TGF-β) and stromal cell-derived factor-1 (SDF-1), both of which are activators of the TGF-β signaling pathway. Additionally, TGF-β pathway activation in SCC-derived CAFs enhances LIF expression and induces a pro-invasive CAF subtype through JAK/STAT3 signaling^[15].

The expression of these IL-6-like cytokines is regulated by nuclear factor-κB (NF-κB), which can be activated through the STAT3-related pathway^[17]. This interaction establishes a self-sustaining autocrine loop involving IL-6-like cytokines, STAT3, and NF-κB in CAFs, thereby sustaining their tumor-promoting phenotypes in breast cancer^[18].

Other factors that promote the expression of IL-6-like cytokines also initiate and sustain phenotypes driven by this autocrine loop. In oral squamous cell carcinoma (OSCC), epiregulin derived from fibroblasts enhances the secretion of IL-6 in both CAFs and tumor cells, initiating the transition from fibroblasts to CAFs^[19]. In pancreatic cancer, IL-1 secreted by tumor cells promotes the autocrine of IL-1, IL-6 and LIF through the NF-κB signaling pathway, thereby activating the IL-6-like-cytokines/STAT3/NF-κB signaling cascade in CAFs^[20–22]. The CAF subtype activated by IL-1 in pancreatic cancer is classified as inflammatory CAF (iCAF), which is characterized by low expression of α-smooth muscle actin (α-SMA) and high expression of inflammatory cytokines. These iCAFs are predominantly located in the peripheral regions of tumor tissue and play a critical role in regulating tumor inflammation, immunosuppression, and matrix remodeling, all of which contribute to the progression of pancreatic ductal adenocarcinoma (PDAC)^[23,24]. TGF-β secreted by tumor cells activates the TGF-β signaling pathway in CAFs located in adjacent regions, inhibits the expression of interleukin-1 receptor 1 (IL-1R1), and prevents the formation of the iCAF phenotype^[20]. Although both subtypes possess matrix remodeling abilities, the iCAF subtype may represent a phenotype distinct from the invasive-promoting CAFs directly induced by IL-6-like cytokines, as reflected by differences in α-SMA expression and their differential relationship with the TGF-β pathway. The molecular mechanism remains unclear, as similar stimuli can lead to distinct molecular phenotypes and histological behaviors.

Several other factors have also been found to activate the STAT3 pathway in CAFs, thereby inducing the formation of specific phenotypes. For example, in colorectal cancer (CRC), a pro-angiogenic podoplanin (PDPN)⁺ CAF subtype has been identified, which sustains its phenotype through autocrine C-C motif chemokine ligand 2 (CCL2)-mediated STAT3 activation^[25].

Additionally, the senescence of fibroblasts^[26] and specific inflammatory environments^[27] can elevate intracellular levels of reactive oxygen species (ROS), triggering the activation of the STAT3 pathway and promoting the formation of distinct CAF phenotypes. These CAF phenotypes have been demonstrated in both gastric and lung cancers to not only regulate matrix remodeling to facilitate tumor invasion and migration, but also secrete various senescence-associated secretory phenotypes (SASP) factors, further promoting cancer progression^[26,27].

NF-κB signaling pathway

NF-κB refers to a series of protein complexes primarily composed of Rel subfamily proteins, such as RelA (p65) and RelB, as well as NF-κB subfamily proteins like NF-κB1 (p105/p50) and NF-κB2 (p100/p52). In its inactive state, NF-κB is sequestered in the cytoplasm by the inhibitor of NF-κB (IκB). Upon activation by extracellular cytokines, such as IL-1 and tumor necrosis factor α (TNF-α), the inhibitor of NF-κB kinase (IKK) phosphorylates IκB, leading to its ubiquitination and degradation. This process releases the NF-κB complex, allowing it to translocate to the nucleus, where it regulates the transcription of target genes. These target genes encode a wide range of anti-apoptotic proteins, cytokines, and adhesion factors. Furthermore, NF-κB also interacts with signaling involving other transcription factors such as STAT3, p53, and ETS-related gene (ERG)^[28].

Previous studies have demonstrated the constitutive activation of NF-κB in CAFs. The activators include various cytokines, such as IL-1 in PDAC and early-stage SCC^[20,29], as well as three inflammatory cytokines (IL-1α, IL-1β, and TNF-α) in gastric cancer (GC)^[27]. Moreover, several non-cytokine proteins have been implicated, including Pyruvate kinase M2 in GC cells^[30], type IV collagen α1 (COL6A1) in osteosarcoma^[31], as well as collagen type XI alpha 1 (COL11A1)^[32] and CircRNA CUL2 in PDAC-derived CAFs^[33].

NF-κB activation in CAFs upregulates the expression of various pro-inflammatory chemokines, complement^[34] and cytokines such as IL-6, IL-1, IL-8^[33]. The IL-6-like cytokines secreted by these CAFs can activate the JAK/STAT3 pathway, establishing an autocrine cycle that sustains their capacity to secrete inflammatory factors^[18].

In addition to cytokines, other environmental factors can also induce NF-κB activation in CAFs. Hypoxia-induced NF-κB activation in CAFs has been shown to promote the secretion of growth factors that facilitate tumor epithelial-mesenchymal transition (EMT) in pancreatic cancer^[35]. Furthermore, calcium influx mediated by the transient receptor potential cation channel subfamily C member 3 (TRPC3) has been demonstrated to activate NF-κB, inducing a CAF phenotype in adipose-derived mesenchymal stem cells in colon cancer^[36].

Remarkably, recent studies in GC have demonstrated that the NF-κB pathway plays a key role in the transmission and diffusion of the CAF phenotype^[37].

ROS in normal fibroblasts (NFs) activate the NF-κB pathway, promoting CAF activation via inflammatory cytokine secretion and microenvironment remodeling. The subsequent upregulation of hypoxia-inducible factor-1α (HIF-1α) and cyclooxygenase-2 (COX-2) enhances glycolysis, providing essential ROS to maintain this CAF phenotype in a positive feedback loop. Dependent on this process, the CAF phenotype efficiently spreads to surrounding resident NFs, further promoting the dissemination of cancer cells^[37]. Additionally, ROS have been shown to activate STAT3 in CAFs, suggesting that this spreading process may also involve the JAK/STAT3 signaling pathway^[26,27].

According to the above findings, the NF-κB pathway in CAFs is closely interconnected with the JAK/STAT3 pathway. Both pathways are activated by distinct signals and exhibit crosstalk that promotes their sustained activation. This crosstalk enhances and maintains the capability of CAFs to express inflammatory factors, thereby fostering the inflammatory response and driving a range of related processes in cancer. In the majority of studies, NF-κB-activated CAFs have been demonstrated to exhibit a tumor-promoting phenotype. However, recent research in prostate cancer has identified a type of Lym-CAF activated through the NF-κB pathway by TNF-α and IFNγ derived from immune cells. This type of CAF is capable of activating CD8+ T cells, thereby exerting an anti-tumor effect^[38].

TGF-β signaling pathway

The TGF-β signaling pathway is primarily activated by TGF-β1/2/3 and bone morphogenetic proteins (BMPs). The SMAD transcription factors are activated by membrane-bound kinase receptor complexes, which in turn regulate target gene expression^[39]. TGF-β membrane receptors also activate other signaling pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt.

The critical role of this pathway in tissue fibrosis has been extensively studied^[39,40]. CAF phenotypic transition, as a differentiation process of fibroblasts, is also regulated by the TGF-β pathway^[41]. Activation of the TGF-β pathway induces metabolic reprogramming^[41] and enhances stromal responses^[42], mediating the formation of myofibroblast CAFs and promoting cancer invasion and metastasis^[43]. Another study has found that TGF-β-activated fibroblasts can enhance the survival of metastatic cells by activating the GP130/STAT3 signaling pathway, thereby further promoting CRC metastasis^[44].

Heat-shock factor 1 (HSF1) has been identified as a key effector of the TGF-β pathway in CAFs of human breast carcinomas, with its downstream target SDF-1, also acting as an activator of this pathway. The autocrine loop of SDF-1 sustains this CAF phenotype^[45].

The cytokine TGF-β elicits distinct responses in different cell types and environments, which allows it to play a dual role in cancer^[46]. In fibroblasts, TGF-β differentially regulates their terminal differentiation by activating different downstream SMAD proteins. In a fibronectin-rich, low-stiffness matrix, TGF-β induces a fibroblast activation protein-α (FAP)^Hi/α-SMA^Low reactive phenotype, which is involved in ECM synthesis and protein hydrolysis. Conversely, in a collagen type I-rich, high-stiffness matrix, TGF-β induces a FAP^Low/α-SMA^Hi myofibroblast phenotype, which participates in the wound healing through cell contraction and proliferation^[47].

The crosstalk between the TGF-β pathway and other pathways, such as the JAK/STAT3 pathway, may also be influenced by the surrounding environment. In SCC, the TGF-β pathway has been shown to induce the expression of LIF in both fibroblasts and tumor cells. The secreted LIF activates the JAK/STAT3 pathway, leading to the generation of pro-invasive fibroblasts^[15]. In breast cancer, TGF-β and SDF-1 are highly expressed in the CAF phenotype induced by the JAK/STAT3 pathway, suggesting a potential synergistic interaction between these pathways^[48]. Conversely, in PDAC fibroblasts, the TGF-β pathway activated by paracrine signaling from cancer cells inhibits the JAK/STAT3 pathway, leading to the formation of CAF phenotypes that influence tissue fibrosis and matrix synthesis. Further studies are required to determine whether these phenotypic differences result from differential regulation by the TGF-β pathway.

Additionally, the formation of TGF-β pathway-related CAFs is associated with Wnt7a secreted by tumor cells and senescence-related molecules in fibroblasts^[49]. Moreover, the trans-differentiation of various non-fibroblast cells, such as macrophages^[50] and mesothelial cells^[51], into CAFs is also mediated by TGF-β.

MAPK pathway and PI3K/Akt pathway

The MAPK pathway is a signaling cascade mediated by a three-tiered kinase system. This system includes MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK) and MAPK^[52]. This pathway comprises four main branches: the classical extracellular regulated protein kinases (ERK) pathway, the c-Jun N-terminal kinase (JNK) pathway, the p38/MAPK pathway, and the ERK5 pathway, each of which has distinct functions^[52]. The p38/MAPK pathway primarily regulates inflammatory responses. Its activation in fibroblasts has been demonstrated to upregulate the expression of pro-inflammatory genes, enhance proliferation and migration, and promote the formation of the CAF phenotype in breast cancer, lung cancer, and melanoma^[53–55]. Further studies indicate that the formation of the CAF phenotype is a p38/MAPK-dependent process induced by TGF-β, TNF-α, Wnt, or epidermal growth factor receptor (EGFR) signals^[53,55].

PI3K/Akt pathway transduction is initiated by PI3K binding to growth factor receptors, leading to Akt activation, which subsequently phosphorylates various downstream substrates, including IKK, Apoptosis Signal-regulating kinase 1 (ASK1), and mammalian target of Rapamycin (mTOR). The diversity of Akt substrates determines its central role within the Ser/Thr kinase network of the PI3K/Akt pathway, enabling extensive regulation of cellular processes. Additionally, the phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a crucial negative regulator by mediating the dephosphorylation of Akt and inhibiting its activity^[56].

The CAF phenotype activated by the PI3K/Akt pathway is primarily involved in matrix remodeling. In breast cancer, complement component 3a (C3a) and lysyl oxidase-like 2 (LOXL2) have been shown to induce the formation of this matrix-associated phenotype^[57,58]. LOXL2-induced CAFs have also been identified in prostate cancer, where they secrete LOXL2 in an autocrine manner, activating surrounding fibroblasts^[59]. Additionally, miRNA-21 secreted by hepatocellular carcinoma cells targets PTEN in hepatic stellate cells, enhancing PI3K/Akt signaling activation and promoting the transition of stellate cells into CAFs. This CAF phenotype secretes factors related to angiogenesis and matrix remodeling^[60].

During CAF formation, the two pathways have been demonstrated to function synergistically. In gastric cancer, inflammatory factors, such as IL-17, IL-23, and TNF-α secreted by tumor-educated neutrophils (TENs), activate the Akt and p38 pathways in mesenchymal stem cells (MSCs), driving their trans-differentiation into CAFs. These CAFs exhibit significantly enhanced proliferation and migration abilities, accompanied by high expression of IL-6, matrix metallopeptidase 9 (MMP9), TGF-β, and vascular endothelial growth factor (VEGF), all of which contribute to tumor growth and metastasis^[61].

Wnt/β-catenin, Hippo/YAP, Notch and Hedgehog pathways

The Wnt/β-catenin, Hippo/YAP, Notch and Hedgehog pathways demonstrate diverse forms of crosstalk, orchestrating embryonic development and organogenesis^[62].

The canonical Wnt/β-catenin pathway is initiated by secreted Wnt proteins, which trigger signaling cascades that inhibit the formation of β-catenin degradation complexes. This inhibition results in the accumulation of β-catenin proteins, which then translocate to the nucleus, where they bind to transcription factors to initiate the transcription of target genes. In CRC, breast cancer, and head and neck SCC, activation of the Wnt/β-catenin pathway has been demonstrated to induce the formation of invasion-promoting CAFs^[63,64]. In addition to resident fibroblasts adjacent to tumors, Wnt/β-catenin signaling has also been shown to mediate the trans-differentiation of adipocytes into a fibroblastic phenotype, thereby endowing them with the capacity to promote tumor invasion^[64]. These Wnt-activated CAFs secrete Wnt ligands to promote cancer progression. This persistent paracrine signaling loop established between the tumor and CAFs facilitates cancer progression^[65,66].

Additionally, the activity level of the Wnt pathway has been found to differentially regulate CAF phenotypes. In CRC, the high level of Wnt signaling promotes the formation of myofibroblast CAFs (myCAFs), which support tumor growth, whereas the low level of Wnt activity induces the formation of iCAFs, which promote tumor invasion^[67].

The Hippo pathway blocks the transcriptional activation of downstream effectors YAP/TAZ by a cascade of kinase phosphorylation reactions^[68]. During the formation of the CAF phenotype, the Hippo pathway regulates the activation of Src kinase family and the contraction of actin cytoskeleton, enabling CAFs to promote matrix stiffening, angiogenesis, and tumor invasion. Meanwhile, matrix stiffening can further enhance YAP activation in CAFs, helping to sustain the CAF phenotype^[69–73]. Interestingly, YAP1 has been identified as a molecular switch between two phenotypes of CAFs in prostate cancer: Lym-CAF and ECM-CAF. The activation of YAP1 facilitates the formation of the ECM-CAF phenotype while inhibiting the activation of NF-κB p65 through direct interaction with IKKα, thereby preventing the development of the Lym-CAF phenotype^[38].

The Notch pathway mediates signal transduction through direct cell–cell interactions, initiating a three-step proteolytic cleavage process that releases transcriptionally active Notch protein fragments. In the precancerous stage, the absence of Notch signaling induces fibroblast activation, contributing to tumorigenesis^[74,75]. During tumor progression, activated Notch signaling via the downstream TGF-β pathway mediates CAF formation. In ductal carcinoma in situ (DCIS), Notch pathway activation induces a platelet-derived growth factor receptor alpha (PDGFRα)^Low/PDGFRβ^Hi CAF phenotype, which is characterized by elevated expression of matrix remodeling enzymes and TGF-β ligands that facilitate the transition from DCIS to invasive cancer^[76]. In CRC models, Notch signaling has been shown to mediate the trans-differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into CAFs^[77].

The Hedgehog pathway is driven by secreted Hedgehog proteins, and mediated by two transmembrane proteins, Patched (Ptc) and Smoothened (SMO). The Hedgehog ligands primarily include Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH)^[78]. Among these ligands, epithelial-derived SHH ligand has been shown to activate adjacent fibroblasts and other stromal cells, promoting fibrous stromal hyperplasia in various solid tumors^[79,80]. However, this hyperplastic stroma tends to inhibit tumor progression. HH activation in CAFs has been demonstrated to inhibit tumor growth in colon cancer^[81]. SHH-deficient PDAC exhibits reduced stromal proliferation, but enhanced invasive, proliferative, and angiogenic capabilities^[82]. Studies on HH signaling in the tumor stroma have also revealed that downregulation of HH signaling accelerates tumor progression, whereas its excessive activation can suppress tumor initiation and development through BMP signaling and by restricting colonic stem cell characteristics^[83]. On the other hand, the increased stromal fibrosis induced by HH signaling can impede chemotherapeutic drug delivery and immune cell infiltration, thereby creating obstacles for cancer treatment^[84,85].

These signaling pathways also collaborate in CAF phenotypic modulation. The Notch, Wnt, and Hedgehog pathways collectively regulate fibroblast proliferation and their transition into myofibroblast during injury and inflammation^[86]. The Wnt/β-catenin pathway is co-activated with YAP/TAZ by the HSF1 effector Dickkopf-3 (DKK3)^[87]. Wnt/β-catenin activation significantly enhances the nuclear translocation of YAP, enabling stromal fibroblasts to acquire the ECM-remodeling CAF phenotype and thereby accelerating tumor growth and invasion in melanoma^[88].

Other signaling pathways

In addition to the major pathways that have been extensively studied, several other pathways also contribute to the formation of CAF phenotypes.

Growth factors, as primary extracellular regulators of cell growth and differentiation, exert significant effects on fibroblast differentiation and phenotype modulation. CAF formation is clearly stimulated by growth factors such as TGFs, EGFs, PDGFs, fibroblast growth factors (FGFs) and hepatocyte growth factors (HGFs), which accelerate tumorigenesis, growth, and invasion^[89,90]. CAFs induced by PDGF signaling have been shown to suppress CD8+ T cell activity, leading to localized immune suppression in PDAC^[91]. Additionally, the trans-differentiation of pericytes into CAFs has been found to be mediated by PDGF signaling. The PDGF-BB ligand secreted by tumor cells binds to platelet-derived growth factor receptor beta (PDGFRβ) on pericytes, recruiting them from blood vessels to tumor regions and driving the trans-differentiation process^[92]. Pericytes co-expressing FAP and PDGFRβ have also been identified in clinical glioblastoma (GBM) specimens and mouse model samples^[93].

Certain chemokine signals also contribute to the formation of the CAF phenotype. In PDAC, the receptor for chemokine C-X-C motif ligand 3 (CXCL3), CXCR2, is predominantly expressed in CAFs. The CXCL3-CXCR2 axis induces the transition of fibroblasts into myCAFs, facilitating PDAC metastasis^[94]. C-C chemokine ligand 5 (CCL5), which is significantly upregulated in CAFs, regulates migratory capacity and matrix metalloproteinase expression by activating αvβ3 integrin and downstream signaling pathways, including PI3K/Akt, MAPK/ERK, and NF-κB^[95]. In ovarian cancer, specific miRNAs have been identified as mediators of CCL5 and CXCL12β, driving fibroblast reprogramming into a specific CAF phenotype^[96,97]. DNA-damage-related Activin A and COX-2 can stimulate CAF formation by promoting prostaglandin E2 secretion, which enhances tumor proliferation, DNA damage, glycolysis, matrix remodeling, angiogenesis, and immune infiltration^[98].

In addition, signaling pathways related to lipid metabolism and glycolysis regulate the metabolic reprogramming of CAFs^[99,100]. Cdc42EP3/BORG2, which is associated with actin and septin networks, modulates cytoskeletal rearrangements of CAFs^[101]. These pathways are also crucial for forming and sustaining CAF phenotypes.

The activation factors, downstream signaling, and driven CAF phenotypic differences of the above-mentioned signaling pathways in CAFs are summarized in Figure 1.

Research advances on drugs targeting the CAF-phenotypic-modulation

Therapeutic strategies targeting CAFs

Tumor therapy targeting CAF initially focused on exploiting universal biomarkers to broadly eliminate CAF populations. One of the primary strategies studied involves targeting FAP for the specific recognition and elimination of CAF cells^[102,103]. However, some studies have reported significant side effects from systemic treatments targeting FAP, including muscle loss, bone toxicity, and cachexia^[104]. Furthermore, the depletion of the entire CAF population has been found to potentially accelerate tumor progression, as certain CAF phenotypes exhibit tumor-restraining effects^[11,82,105]. For example, CD105^neg CAFs identified in PDAC have been shown to inhibit pancreatic cancer progression by supporting anti-tumor immunity^[106]. This finding corroborates previous research on the immune-suppressive effects resulting from CAF depletion^[105]. Similar CAF subtypes that promote anti-tumor immunity have also been discovered in breast cancer. Additionally, Meflin-positive CAFs, which express the glycosylphosphatidylinositol-anchored protein Meflin, have been identified in PDAC and shown to suppress the growth and invasive features of xenografted tumors^[107]. Given the substantial variability in biomarker expression across different CAF phenotypes, identifying specific targets to selectively eliminate tumor-promoting CAFs remains a considerable challenge.

To specifically target the tumor-promoting effects of CAFs, several novel therapeutic strategies have been developed. For example, monoclonal antibodies targeting tumor-promoting ligands secreted by CAFs can block CAF-tumor interactions^[23,108,109]. However, since these interactions involve numerous cytokines, this strategy may be more suitable as an adjunct to chemotherapy or immunotherapy.

Directly targeting the formation and maintenance processes of tumor-promoting CAF phenotypes may represent a more promising option. An increasing number of studies support the tumor-inhibitory effects of this strategy. For instance, retinoic acid has been shown to block the transition of PSCs into CAFs and reduce IL-6 secretion, thereby inhibiting tumor cell migration and EMT^[110]. All-trans retinoic acid (ATRA) can restore the quiescent state of PSCs that have been activated into CAFs, enhancing the therapeutic effect of gemcitabine (GEM)^[111,112]. Since the formation and maintenance of CAFs involve multiple signaling pathways, all inhibitors of these pathways may exert tumor-suppressive effects by targeting CAFs, although their practical effects on CAFs require further validation. These therapeutic strategies targeting CAFs are summarized in Figure 2.

However, it should be noted that these signaling pathways also play essential roles in normal tissues; thus, their inhibitors may cause corresponding side effects or potential on-target toxicities. Owing to the critical functions of JAK/STAT signaling in hematopoiesis and immunity, JAK inhibitors such as ruxolitinib may induce immunosuppression, increase the risk of viral infections, and cause anemia, thrombosis, and thrombocytopenia^[13,113]. TGF-β regulates valvular interstitial differentiation, skin wound healing, and vascular wall integrity; accordingly, TGF-β inhibitors such as galunisertib have shown cardiotoxicity, hyperkeratosis, fatigue, and anemia in clinical trials, along with disruption of immune homeostasis^[114]. Given the roles of Wnt signaling in bone, the hematopoietic system, and the gastrointestinal tract, its inhibition leads to myelosuppression, increased fracture risk due to reduced bone mineral density, and gastrointestinal toxicities such as diarrhea^[115]. PI3K/Akt and MAPK signaling serve as fundamental survival/proliferation signals in nearly all proliferative normal tissues; broad inhibition of these pathways therefore results in multi-system toxicities affecting metabolism^[116], the cardiovascular system^[117], skeletal muscle, and the eye^[118]. Consequently, achieving therapeutic selectivity requires strategies such as local delivery, drug conjugation, exploitation of differential pathway dependencies, or precise targeting via CAF markers. For instance, certain CAF-targeting nano-delivery systems can precisely localize and release drugs, thereby avoiding systemic toxicity^[119]. Drug enrichment within the tumor stroma can also be achieved through the enhanced permeability and retention (EPR) effect and stromal affinity, thereby reducing systemic exposure^[120]. Moreover, CAF activation has been shown to depend on substantially elevated PI3K/Akt/mTOR^[121] and YAP/TAZ^[69] pathway activities relative to NFs; exploiting this “differential dependency window” may permit CAF-selective inhibition at doses below the threshold of systemic toxicity. These selective delivery strategies warrant further validation and development. Integrating the aforementioned pathway inhibitors involved in CAF phenotypic modulation with these selectivity strategies would represent a major breakthrough in CAF-directed cancer therapy, as it could resolve the challenge of precisely targeting tumor-promoting CAFs while sparing normal tissues.

Targeting JAK/STAT3 pathways

Some JAK/STAT3 inhibitors have demonstrated anti-tumor effects by inhibiting the formation of tumor-promoting CAFs and enhancing the efficacy of chemotherapy and immunotherapy. Tocilizumab, which binds to IL-6R, blocks IL-6-triggered JAK/STAT3 activation, reducing proliferative fibroblasts and enhancing the efficacy of combination therapy with GEM and nanoparticle albumin-bound paclitaxel (nab-PTX) in pancreatic cancer, as demonstrated in a phase 1 clinical trial^[122]. Studies conducted in vitro and in mouse models of pancreatic cancer have shown that the JAK inhibitor ruxolitinib suppresses STAT3 phosphorylation in PSCs, inhibiting cell proliferation and α-SMA expression^[123]. The combination of ruxolitinib and trametinib (a mitogen-activated protein inhibitor) has been found to reduce both iCAFs and myCAFs in the Ptf1a^cre/+; LSL-Kras^G12D/+; Tgfbr2^flox/flox (PKT) mouse model and in a metastatic, chemotherapy-refractory PDAC patient, thereby improving the therapeutic effect of Nivolumab (a PD-1 inhibitor) on PDAC^[124].

Some natural compounds have also been identified as JAK/STAT3 inhibitors, influencing the phenotype and function of CAFs. Cucurbitacin I (JSI-124) has been demonstrated to inhibit the IL-6/STAT3/NF-κB signaling loop in mammary myCAFs, thereby inactivating CAFs and suppressing their tumor-promoting capacities^[125]. A novel polysaccharide extracted from Lentinus edodes, MPSSS, has been found to inhibit the JAK2/STAT3 signaling pathway via Toll-like receptors. This compound suppresses TGF-β1 secretion by CAFs and reduces drug resistance in prostate cancer^[126].

In addition, various identified JAK/STAT3 inhibitors may also participate in modulating CAF phenotype, although their specific effects remain to be further investigated:

●JAK inhibitors

•Approved by the U.S. Food and Drug Administration (FDA): tofacitinib, pacritinib, and baricitinib^[127,128].

•Natural products: tagalide A, resveratrol, and flavopiridol, etc^[129].

●STAT3 inhibitors

•Src homology 2 (SH2) domain inhibitors: e.g., stattic^[129].

•Decoy oligonucleotides: e.g., AZD9150^[129].

•STAT3 phosphorylation inhibitors: e.g., LL-12^[129].

•Natural compounds: esculentoside A, catechol, and galiellalactone, etc^[128].

●IL-6/IL-6R axis inhibitors (blocking upstream activation signals of JAK/STAT3)

•Anti-cytokine/receptor antibodies: siltuximab, sarilumab, diacerein, etc^[128,129].

•sgp130-Fc fusion protein: e.g., olamkicept^[128,129].

•Receptor modulators: raloxifene and bazedoxifene, etc^[128,129].

•Natural compounds: galangin, quercetin, and luteolin, etc^[128].

Notably, curcumin has been widely reported to inhibit the JAK/STAT3 pathway^[130]. However, concerns regarding its stability, reactivity, and bioavailability suggest that these findings should be interpreted with caution^[131].

Collectively, these JAK/STAT3 pathway inhibitors may modulate CAFs by downregulating downstream inflammatory factors and matrix-remodeling enzymes, thereby attenuating tumor aggressiveness, drug resistance, and immune suppression.

Targeting TGF-β pathways

The potential of therapeutic strategies targeting the TGF-β pathway for anti-tumor and anti-fibrosis applications has been supported by extensive clinical data. TGF-β-targeted inhibitors primarily include neutralizing antibodies, small molecule inhibitors, ligand traps, receptor kinase inhibitors, antisense oligonucleotides, and allogeneic tumor cell vaccines^[40,132].

The effects of TGF-β ligand inhibitors on CAFs have been demonstrated. The ligand trap, TGF-β-TRAP, modulated CAF heterogeneity, reduced the immune-suppressive effects of the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in PDAC mouse models^[133]. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), functioning as a decoy TGF-β receptor, has been found to block the trans-differentiation of BMSCs into CAFs and to negate their tumor-promoting effects in both in vitro and in situ breast cancer xenograft models^[134].

Several TGF-β inhibitors have also been confirmed to exert their effects by influencing CAFs. Blocking TGF-β signaling with the TGF-β R2 monoclonal antibody 2G8 in PDAC mouse models inhibited IL-6 secretion by CAFs, alleviated the suppression of natural killer cells, and significantly reduced tumor proliferation, metastasis, and dissemination^[135]. Preliminary studies at the cellular level have found that the TGF-β receptor inhibitor SB525334 can reverse CAF-induced docetaxel resistance in prostate cancer^[112]. Subsequently, studies in vitro and in tumor-bearing mice demonstrated that the combination of SB525334 and docetaxel suppressed fibrotic activation in pancreatic myCAFs and reduced cell proliferation^[136]. Another TGF-β1 receptor inhibitor, galunisertib, in combination with the transforming growth factor-β-activated kinase 1 (TAK1) inhibitor OXO, was found to block TGF-β and NF-κB signaling pathway activation mediated by IL-1β/TGF-β1 in patient-derived xenograft mouse models. This inhibited fibroblast activation and reduced the metastatic potential of colon cancer cells^[137]. Additionally, TAK1 inhibition was shown to convert tumor-promoting CAFs into a tumor-suppressive phenotype in three-dimensional cultures of pancreatic cancer and in organoid transplantation mouse models^[138].

Targeting other signals that crosstalk with the TGF-β pathway also plays an inhibitory role in CAFs. The binding of the vitamin D receptor (VDR) to ligands such as calcipotriol inhibits the activation of stellate cells. In a mouse model of chronic pancreatitis, VDR activation reduced the expression of cancer-related marker genes and decreased inflammation and fibrosis, potentially by blocking the TGF-β pathway in fibroblasts through genomic competition^[111]. Eribulin, a microtubule-targeting agent approved by the FDA for breast cancer treatment, has been shown to normalize PDAC-associated fibroblasts in vitro by suppressing phosphorylated SMAD2/3 levels^[139]. Polo-like kinase 1 (PLK1) can form a positive feedback loop with TGF-β, contributing to fibroblast activation. Targeted inhibition of PLK1 in CAFs of cholangiocarcinoma has been demonstrated to disrupt this loop, achieving an anti-tumor effect^[140]. Additionally, the angiotensin inhibitor losartan and Angiotensin receptor blocker (ARB) have been found to inactivate CAFs and reduce collagen production by inhibiting angiotensin and downstream TGF-β1 signaling^[141].

Given the role of the TGF-β pathway in regulating the transition between different CAF phenotypes, there is significant potential to develop highly promising CAF-targeted therapies based on TGF-β inhibitors.

Targeting MAPK and PI3K/Akt pathways

The close relationship between the p38/MAPK and PI3K/Akt/mTOR pathways and tumor therapy is well recognized. However, there are limited studies that clarify their roles in fibroblast activation.

Chemical synthesis inhibitors of p38 are primarily categorized as ATP site-binding and non-ATP site-binding agents, which inhibit p38 activity by disrupting its interaction with ATP and other proteins^[142]. These inhibitors have been shown to reduce the synthesis of inflammatory factors like TNF-α and IL-1^[143]. Notably, the tyrosine kinase inhibitor pexmetinib decreases IL-1α secretion from PDAC tumor cells, thereby diminishing iCAFs induced by IL-1α in the PTK mouse model^[144]. Additionally, the natural compound ligustilide, an extract from Angelica and Chuanxiong, impairs the angiogenic capabilities of CAFs via the Toll-like Receptor 4 (TLR4)-p38/ERK/JNK-AP-1 pathway in prostate cancer^[145]. Furthermore, miRNAs like miR-340-5p have been found to target the p38/MAPK pathway to inhibit fibroblast proliferation and activation in lung fibrosis^[146].

The main activators of the PI3K/Akt pathway include growth factors, hormones, and cytokines. Blocking these activation signals can significantly suppress the pathway. CAFs in PDAC have been found to selectively express somatostatin receptor sst1, and the somatostatin analogue SOM230 inhibits the synthesis of CAF-secreted proteins, such as IL-6, by targeting the PI3K/Akt/mTOR/4E-BP1 signaling pathway^[147,148].

PI3K inhibitors can be categorized into three main types: Pan-PI3K Inhibitors, which inhibit the catalytic activity of all class I PI3K subtypes (PI3Kα, β, γ, and δ); isoform-Specific PI3K Inhibitors, which target specific PI3K subtypes; dual PI3K/mTOR Inhibitors, which target all PI3K subtypes as well as mTORC1 and mTORC2^[149,150]. In addition, several novel drugs are in development. One example is CUDC-907, a newly synthesized small molecule that inhibits both histone deacetylases and PI3K. It has been shown to inhibit the proliferation and migration, and to cause cell cycle arrest of TGF-β1-induced CAF phenotypes^[151].

Akt kinases can be inhibited by various kinase inhibitors and kinase receptor inhibitors. Regorafenib, a multi-kinase inhibitor, induces apoptosis in gastrointestinal CAFs by inhibiting Akt phosphorylation, thereby affecting macrophage infiltration^[152]. Anlotinib, an antiangiogenic tyrosine kinase receptor inhibitor, reduces the cell viability of CAFs and promotes apoptosis in lung adenocarcinoma^[153].

There are also many natural products that have been proven to regulate the PI3K/Akt pathway, such as capsaicin, and salidroside^[154]. However, their role in CAFs has not been studied.

Targeting other pathways

Inhibiting certain other pathways has also been shown to impede tumor progression by inhibiting the formation and function of CAFs.

For example, melatonin has been demonstrated in cellular and animal models to reduce IL-8 expression in CAFs by inhibiting NF-κB, thereby reversing the promoting effect of CAFs on EMT in breast cancer cells^[155].

Targeting CXCR4/CXCL12 signaling with plerixafor can delay fibrosis progression, thereby reducing resistance to immune checkpoint therapy in metastatic breast cancer^[156].

Spatial analysis of surgically obtained tumor tissue samples combined with cells co-culture studies revealed that in ovarian clear cell carcinoma, inhibiting PDGFR signaling with the receptor tyrosine kinase inhibitor ripretinib reduces CAF viability and their capacity to activate HIF-1α signaling in surrounding tumor tissues, thereby enhancing the efficacy of cisplatin^[157]. Another receptor kinase inhibitor, imatinib, targets PDGFR signaling to convert the CAFs isolated from primary lung cancer into a normal fibroblast phenotype^[158]. The EGFR/erb-b2 receptor tyrosine kinase 2 (ERBB2) inhibitor (ERBBi) neratinib was found to reduce EGFR signaling-activated myCAFs and inhibit PDAC metastasis in PDAC tumor-bearing mice^[159].

When Hippo signaling is inhibited by ARBs in intrahepatic cholangiocarcinoma (iCCA), the ability of CAFs expressing the ARB receptor AGTR1 to secrete Microfibrillar Associated Protein 5 (MFAP5) is impaired. This suppression of MFAP5-mediated CAF-tumor interaction reduces the aggressiveness of iCCA^[160].

The natural compound Bruceine D blocks Notch-1-Jagged/NF-κB (p65) signaling in breast cancer, weakening the TNF-α-mediated interaction between breast cancer cells and CAFs, thereby inhibiting tumor metastasis^[161].

Unlike the previously mentioned tumor-promoting CAFs, those induced by Hedgehog signaling are thought to inhibit tumor progression. Deleting HH signaling in mice or blocking it with small molecules like IPI-926 or SMO antagonists reduces stromal content in pancreatic cancer, decreases α-SMA-positive myCAFs, and increases the proportion of iCAFs^[162]. This process makes the tumor more aggressive and immune-suppressive^[82,162,163]. Excessive activation of the Hedgehog signaling pathway has been shown to suppress tumor initiation and growth in a mouse model of PDAC and colitis-associated colon cancer^[83,162]. However, some in vivo studies in mice have found that Hedgehog signaling inhibitors, such as Patched-1 and IPI-926, can reduce fibrosis in tumor tissues, facilitating chemotherapeutic drug delivery^[84] and immune cell infiltration^[85], thereby enhancing the efficacy of chemotherapy and immunotherapy. Therefore, therapeutic strategies targeting Hedgehog inhibition need to be combined with chemotherapy or immunotherapy.

Conclusion and prospect

Heterogeneity is a defining characteristic of CAFs. Some subtypes exert a tumor-restraining effect, while others promote tumor progression. Due to these opposing roles, certain targeted therapies aimed at eliminating the entire CAF population may inadvertently accelerate tumor progression^[11]. Therefore, selectively eliminating or normalizing tumor-promoting CAFs represents an important strategy for targeting CAFs in cancer therapy.

Eliminating tumor-promoting CAFs requires phenotype-specific targets. However, due to limited studies on CAF subtypes, suitable targets that avoid harming other cells remain unidentified. As the plasticity of CAF phenotypes becomes increasingly recognized^[3,8,20,22], normalizing tumor-promoting CAFs shows promising therapeutic potential. In-depth studies of the CAF phenotypic transition are gradually elucidating the roles of various signaling pathways and their associated CAF phenotypes. These findings provide a solid foundation for the therapeutic strategies that target these signaling pathways to reprogram CAFs into a quiescent or tumor-restraining state.

However, only a limited number of pathway inhibitors have been investigated in CAFs. The effects of pathway inhibitors on CAFs remain a significantly underexplored research area. Notably, these pathway inhibitors may also affect normal tissue function; therefore, strategies to achieve selective drug action, such as nano-delivery systems capable of specifically targeting CAFs, warrant further development. Many natural compounds, such as resveratrol and catechins, generally exhibit mild activity and low toxicity, offering certain advantages in drug safety. Moreover, they can act on multiple signaling pathways and may exert broader inhibitory effects on CAFs; however, issues regarding their bioavailability and metabolic stability also need to be considered.

Although remodeling CAF phenotypes with pathway inhibitors represents a promising therapeutic strategy, its limitations should also be properly recognized.

In the actual tumor microenvironment, CAFs are continuously exposed to multiple stimuli that can drive phenotypic activation^[1]. Single-pathway inhibition may therefore remodel only certain CAF subsets, while other signals could still activate these cells into alternative subtypes. Furthermore, upon drug withdrawal, CAFs may be re-activated by the same stimuli and revert to their original phenotypes, suggesting that long-term administration may be required to sustain phenotypic remodeling. Additionally, some signaling pathways induce CAF activation through epigenetic reprogramming, such as DNA methylation changes driven by TGF-β/SMAD signaling^[164] and hypoxia-induced HIF-1α signaling^[165]. Attenuating the upstream signals that trigger epigenetic reprogramming may prevent the establishment of these CAF phenotypes, but may have limited effects on CAFs in which epigenetic alterations have already occurred. Reversing such epigenetic reprogramming may therefore require the use of corresponding epigenetic inhibitors^[166].

Interventions targeting CAFs may restrain tumor progression rather than completely eliminate tumor cells, and therefore may need to be combined with surgery or other cytotoxic approaches. For example, inhibiting the pro-invasive functions of CAFs could confine tumors within a resectable range. Moreover, attenuating CAF-mediated effects on the ECM, immune cells, and other components of the tumor microenvironment may reduce drug resistance^[167] and immunosuppression^[168]. In addition, the accumulation of platinum-based drugs in the stroma can induce autocrine TGF-β activation in CAFs, promoting a phenotype that confers tumor drug resistance^[169].Combining CAF-targeting drugs with chemotherapy and immunotherapy holds significant promise for enhancing treatment efficacy. This strategy offers substantial potential for future research and clinical applications.

Currently, numerous important CAF subtypes have been identified through single-cell sequencing technology^[170,171], but the mechanisms underlying their phenotypic modulation remain poorly understood. Further research into these subtypes may reveal novel phenotypic modulation mechanisms and pave the way for the development of more targeted therapies.

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