Review Article

Cancer-Associated Fibroblasts in Colorectal Cancer: From Heterogeneity to Therapeutic Targeting

 Seojin Jang^1,*, Chang-Whan Yoon^2,3,*, Seohee Park^1,2, Hyunwoo OH^2,4, Won Sohn^2,4,#, Seok-Hyung Kim^1,5,#

Abstract

Background/Objectives: Colorectal cancer (CRC) remains a major global health burden, with disease progression, metastasis, and therapeutic resistance increasingly attributed to the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) constitute a dominant and functionally heterogeneous population characterized by distinct transcriptional, metabolic, and spatial features compared with normal fibroblasts. CAFs arise from multiple cellular origins, including resident fibroblasts, mesenchymal stem cells, pericytes, and cells undergoing epithelial- or endothelial-to-mesenchymal transition, and exist in diverse functional states such as inflammatory, myofibroblastic, and matrix-producing subtypes.

Methods: This review integrates recent preclinical and clinical studies investigating CAF biology and CAF-targeted therapeutic strategies in colorectal cancer. We analyzed literature addressing CAF origins, heterogeneity, and functional plasticity, as well as emerging therapeutic approaches including fibroblast activation protein (FAP)-targeted antibodies, antibody–drug conjugates, small-molecule inhibitors, and radionuclide-based therapies. Emphasis was placed on mechanisms of action, therapeutic efficacy, resistance mechanisms, and translational challenges.

Results: CAFs actively promote multiple malignant hallmarks in CRC through paracrine signaling and extracellular matrix remodeling, driving metabolic reprogramming, epithelial–mesenchymal transition, invasion, angiogenesis, immune suppression, cancer stemness, and resistance to chemotherapy, radiotherapy, and targeted therapies. While CAF-directed interventions have demonstrated promising preclinical activity, clinical outcomes remain modest due to pronounced CAF heterogeneity, subtype-specific functions, and adaptive plasticity in response to therapeutic pressure. These factors limit durable responses when CAFs are targeted in isolation.

Conclusions: Targeting cancer-associated fibroblasts represents a compelling but complex therapeutic strategy in colorectal cancer. Advancing CAF-directed therapies will require biomarker-guided patient stratification, deeper understanding of CAF subtype dynamics, and rational combination strategies that integrate CAF targeting with immunotherapy, anti-angiogenic therapy, or tumor cell–directed treatments. Such precision-based approaches may enable effective remodeling of the tumor microenvironment and improve therapeutic outcomes in CRC.

Keywords

Colorectal cancer, cancer-associated fibroblasts, tumor microenvironment, Therapeutic Strategies.

Introduction

Colorectal cancer remains one of the most prevalent and deadly malignancies worldwide, with high incidence and significant mortality despite advances in screening and treatment. The tumor microenvironment (TME) plays a critical role in regulating cancer initiation, progression, and metastasis through complex interactions between cancer cells and surrounding stromal and immune components [1]. Among the diverse cellular constituents of the TME, cancer-associated fibroblasts (CAFs) are key components that actively promote tumor growth, invasion, and therapy resistance through paracrine signaling and extracellular matrix remodeling. Their functional diversity and plasticity make them promising targets for novel anticancer therapeutic strategies [2, 3]. Understanding these dynamic interactions provides crucial insights for developing more effective therapeutic strategies. This review provides an overview of the origins of CAFs in colorectal cancer, elucidate their diverse functional roles within the tumor microenvironment, and discusses potential therapeutic strategies targeting these cells.

Morphological and Spatial Heterogeneity of CAFs

Cancer-associated fibroblasts exhibit distinct spatial distribution patterns within colorectal tumors, with their localization closely related to their functional phenotypes. Morphologically, CAFs display characteristic spindle-shaped or stellate appearances with elongated cytoplasmic processes, distinguishing them from the polygonal morphology of epithelial cancer cells [4, 5]. Myofibroblastic CAFs (myCAFs) are predominantly found in close proximity to cancer cell nests at the invasive front, where they form a dense periductal or pericryptal distribution pattern around malignant epithelial structures. In contrast, inflammatory CAFs (iCAFs) typically reside in more distant stromal regions, often located in the central tumor stroma away from direct cancer cell contact [6]. The spatial heterogeneity of CAF subpopulations is further evidenced by their differential distribution across tumor regions, with higher CAF density typically observed in desmoplastic areas characterized by extensive collagen deposition and tissue stiffening [7]. Immunohistochemical staining demonstrates that FAP-positive CAFs show widespread distribution throughout the tumor stroma, whereas other markers such as podoplanin and S100A4 exhibit more restricted localization patterns [8, 9]. Understanding these spatial and morphological characteristics is essential for interpreting CAF functions and developing location-specific therapeutic interventions.

Figure 1. Morphology and localization of CAFs in colorectal cancer. Representative histological H&E images of colorectal tissues, with CAFs indicated by red arrows. A. Normal. B. Inflammation. C. Adenocarcinoma. Scale bars = 100 µm.

Molecular Markers for the Identification of CAFs

Accurate identification and isolation of CAFs from heterogeneous tissue samples requires reliable molecular markers, yet a major challenge remains the lack of universally specific CAF biomarkers, as many commonly used markers are also expressed by other cell types. Nevertheless, several proteins have proven valuable for CAF detection. α-SMA (ACTA2) is the most widely used CAF marker, though it is also expressed by pericytes and smooth muscle cells, and its high expression correlates with poor prognosis in CRC [10, 11]. Fibroblast activation protein (FAP), a serine protease highly expressed in CAFs but largely absent in normal tissues, shows positivity in 98.4% of CRC cases, making it an attractive therapeutic target [12]. Other established markers include fibroblast specific protein-1 (FSP-1/S100A4), a calcium-binding protein associated with CAF motility and metastatic potential [13]. PDGFRα/β, platelet-derived growth factor receptors critical for CAF proliferation and survival [14]. Podoplanin (PDPN), a mucin-type transmembrane glycoprotein associated with tumor invasion and lymphatic metastasis [9]. Vimentin, an intermediate filament protein is one of the key markers that characterize CAFs that indicates the mesenchymal phenotype of CAFs [3].  Beyond these conventional markers, proteomic analyses have identified additional CRC-specific CAF biomarkers including latent TGF-β-binding protein 2 (LTBP2), cadherin 11 (CDH11), olfactomedin-like 3 (OLFML3), and follistatin-like 1 (FSTL1), which may enable more precise CAF characterization in future studies [15].

Figure 2. Immunohistochemical staining of cancer-associated fibroblast marker, FAP Representative IHC images showing fibroblast activation protein (FAP) expression in the tumor stroma of colon cancer specimens. (A–C) FAP staining is predominantly localized in cancer-associated fibroblasts (CAFs) surrounding glandular tumor structures, while epithelial tumor cells show minimal staining. Brown coloration indicates positive FAP immunoreactivity, and nuclei are counterstained with hematoxylin (blue). Scale bars, 100 µm.

Subpopulations and Functional Heterogeneity of CAFs

Cancer-associated fibroblasts represent a highly heterogeneous cell population with distinct molecular signatures and functional specializations that reflect their developmental states and microenvironmental positioning. Single-cell RNA sequencing analyses have identified at least four major CAF subpopulations in colorectal cancer, each characterized by unique transcriptional profiles and biological functions. Progenitor CAFs (proCAFs) constitute a less differentiated subset expressing high levels of IGF1, OGN, and C7, representing an intermediate or early activation state that may serve as precursors for more specialized CAF phenotypes. Inflammatory CAFs (iCAFs) are distinguished by robust expression of chemokines including CCL2, CXCL12, and CXCL14, functioning primarily to orchestrate immune cell recruitment and establish an immunosuppressive tumor microenvironment through paracrine signaling. Myofibroblastic CAFs (myCAFs) exhibit elevated expression of contractile and pericyte-associated markers such as RGS5, MYH11, and ACTA2 (α-smooth muscle actin), reflecting their role in extracellular matrix contraction and physical remodeling of the tumor stroma. Mature or matrix CAFs (matCAFs) are characterized by high expression of COL10A1, CTHRC1, and POSTN (periostin), indicating their specialized function in extensive collagen deposition and ECM protein production that drives desmoplastic reactions [16]. These distinct subpopulations coexist within individual tumors and exhibit spatial segregation, with myCAFs typically localizing near cancer cells while iCAFs occupy more distant stromal regions [6, 17]. The balance and interplay among these CAF subtypes significantly influence tumor behavior, with their relative proportions correlating with clinical outcomes and therapeutic responses. Importantly, CAF subpopulations demonstrate remarkable plasticity, with emerging evidence suggesting that they can transdifferentiate between phenotypes in response to changing microenvironmental cues and therapeutic pressures. Understanding this molecular heterogeneity is crucial for developing subtype-specific therapeutic strategies that selectively target pathogenic CAF populations while preserving potentially beneficial stromal functions, highlighting the need for further studies to comprehensively define their origins and biological roles.

Figure 3. Functional roles of cancer-associated fibroblasts (CAFs) in colorectal cancer progression. This schematic illustrates the four major pro-tumorigenic functions of cancer-associated fibroblasts. CAFs promote (1) tumor growth, metabolic support, and proliferation through the secretion of cytokines and growth factors, regulation of glucose, amino acid, and lipid metabolism, and activation of oncogenic signaling pathways including PI3K/AKT and JAK/STAT3. CAF-derived factors additionally drive (2) epithelial-mesenchymal transition (EMT), invasion, and angiogenesis via TGF-β, HGF, matrix-remodeling enzymes such as MMPs, and pro-angiogenic mediators including VEGF, FGF, CXCL12, and PDGF. CAFs further contribute to (3) immunosuppression by recruiting regulatory immune populations (Tregs, MDSCs, and TAMs), expressing immune checkpoint ligands such as PD-L1, and altering metabolic competition that drives T-cell exhaustion. Finally, CAFs facilitate (4) chemotherapy resistance by generating a dense extracellular matrix that impedes drug delivery, activating anti-apoptotic survival pathways, and supporting cancer stem cell maintenance. Together, these mechanisms position CAFs as central regulators of colorectal cancer progression and therapeutic response.

Tumor growth, metabolism, proliferation

Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression in colon cancer through their ability to modulate tumor growth, metabolism, and cell proliferation [18, 19]. One of the primary mechanisms by which CAFs exert these effects is the secretion of a diverse array of cytokines and growth factors, including periostin, IL-6, IL-8, TGF-β, FGF1, FGF3 and HGF [20-23]. These soluble factors activate multiple oncogenic signaling pathways, such as JAK/STAT3, PI3K/AKT, FGF-FGFR4 and HGF-MET, which promote cancer cell proliferation and survival [2, 24, 25]. Beyond direct growth stimulation, CAFs fundamentally reprogram the metabolic landscape of colorectal cancer cells to support their accelerated proliferation. CAFs serve as key regulators of tumor cell metabolism through modulation of glucose, amino acid, and lipid metabolic pathways [26]. Through oxidative stress-induced autophagy, CAFs enhance cancer cell metabolic activity, with tumor cells inducing autophagy and oxidative stress pathways in neighboring fibroblasts [27]. CAF-derived metabolites including branched-chain keto acids and autophagy-derived alanine serve as carbon and nitrogen sources for cancer cells to fuel the tricarboxylic acid (TCA) cycle [28]. CAFs also promote fatty acid oxidation while minimizing glycolysis through upregulation of carnitine palmitoyltransferase 1A, thereby establishing a metabolic environment conducive to tumor growth and invasion [18]. This intricate metabolic crosstalk between CAFs and cancer cells represents a fundamental mechanism by which the tumor stroma actively supports malignant cell proliferation and tumor progression in colorectal cancer.

EMT, invasion and angiogenesis

Cancer-associated fibroblasts (CAFs) play a crucial role in promoting epithelial-mesenchymal transition (EMT), tumor invasion, and angiogenesis within the tumor microenvironment [29]. CAFs secrete a diverse array of cytokines and growth factors, including transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), and stromal cell-derived factor-1 (SDF-1), which induce EMT in cancer cells by suppressing epithelial markers such as E-cadherin while upregulating mesenchymal markers including vimentin and N-cadherin [3, 4, 26, 30]. This EMT program enhances cancer cell plasticity and invasive capacity, enabling tumor cells to detach from the primary mass and migrate through surrounding tissues. CAFs also contribute to tumor invasion through the secretion of matrix metalloproteinases (MMPs) and other extracellular matrix (ECM)-remodeling enzymes, which facilitate the breakdown of structural barriers and enhance cancer cell motility [26, 31]. In the context of angiogenesis, CAFs serve as a major source of pro-angiogenic factors, particularly vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), CXCL12, and platelet-derived growth factor (PDGF), which collectively stimulate endothelial cell proliferation, migration, and new vessel formation. This CAF-induced neovascularization not only supports tumor growth by improving oxygen and nutrient supply but also provides vascular routes that facilitate metastatic dissemination to distant organs [32-34]. The integrated effects of CAF-mediated ECM remodeling, sustained angiogenesis, and paracrine signaling establish these stromal cells as central orchestrators of colorectal cancer progression [35, 36]. Consequently, targeting CAF-mediated mechanisms of invasion, metastasis, and angiogenesis represents a promising therapeutic strategy for patients with advanced colorectal cancer.

Immunosuppression

Cancer-associated fibroblasts (CAFs) play a pivotal role in establishing an immunosuppressive tumor microenvironment that facilitates immune evasion and tumor progression. CAFs secrete immunosuppressive cytokines such as interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-β), which inhibit the activation and proliferation of cytotoxic T lymphocytes and natural killer (NK) cells [22, 37]. Additionally, CAFs recruit immunosuppressive cell populations, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), through the release of chemokines such as CCL2, CXCL12, and CXCL5. CAFs also express immune checkpoint ligands, including programmed death-ligand 1 (PD-L1) and PD-L2, which directly suppress T cell function upon interaction with their cognate receptors.[26, 38-40] Furthermore, CAF-mediated extracellular matrix remodeling creates physical barriers that limit immune cell infiltration into tumor nests, thereby establishing "immune-excluded" tumor phenotypes [26, 41]. The metabolic competition between CAFs and immune cells for nutrients such as glucose and amino acids further contributes to T cell dysfunction and exhaustion [42, 43]. Collectively, these CAF-mediated immunosuppressive mechanisms significantly impair anti-tumor immunity and contribute to resistance against immunotherapeutic interventions, highlighting CAFs as critical targets for enhancing cancer immunotherapy efficacy.

Chemoresistance

Cancer-associated fibroblasts (CAFs) contribute significantly to chemotherapy resistance through multiple interconnected mechanisms that protect tumor cells from cytotoxic agents. CAFs secrete survival factors such as hepatocyte growth factor (HGF) and interleukin-6 (IL-6), which activate pro-survival signaling pathways including PI3K/AKT and MAPK/ERK in cancer cells, thereby reducing their susceptibility to chemotherapy-induced apoptosis [3, 44, 45]. The dense extracellular matrix (ECM) deposited by CAFs creates a physical barrier that impedes drug penetration and distribution within the tumor mass, resulting in suboptimal intratumoral drug concentrations [46]. Furthermore, CAF-derived exosomes containing microRNAs, proteins, and metabolites can be transferred to cancer cells, directly modulating drug efflux pumps and DNA repair mechanisms that counteract chemotherapy effects [47, 48]. CAFs contribute to the maintenance of cancer stem cell populations through the secretion of Wnt ligands, Notch ligands, and other stem cell niche factors, as these stem-like cells exhibit enhanced resistance to chemotherapy [49, 50]. Targeting CAF-mediated resistance mechanisms represents a promising strategy to enhance chemotherapy efficacy and overcome treatment resistance in solid tumors

CAF-Targeted Therapy in Colorectal Cancer: Current Clinical Status and Therapeutic Strategies

Cancer-associated fibroblasts have emerged as critical therapeutic targets in the tumor microenvironment, with multiple preclinical studies demonstrating promising efficacy that have now advanced into clinical evaluation [50]. Early clinical trials targeting FAP with sibrotuzumab (humanized anti-FAP antibody) and Val-boroPro (FAP enzymatic inhibitor) showed safety but demonstrated limited efficacy in metastatic colorectal cancer patients [51, 52]. More recently, OMTX705, a novel anti-FAP antibody-drug conjugate, demonstrated an excellent safety profile in phase I trials with disease control achieved in heavily pretreated microsatellite stable colorectal cancer when combined with pembrolizumab [53]. Novel FAP-targeted radionuclide therapies using radiolabeled FAP inhibitors with isotopes such as 177Lu, 90Y, and 225Ac are currently being investigated in multiple clinical trials, representing a paradigm shift in CAF-targeting strategies [54, 55]. Preliminary evidence suggests that effective CAF-targeted therapies may reverse CAF-mediated immunosuppression through increased CD8+ immune cell infiltration and downregulation of immunosuppressive cytokines [53]. Clinical trials have proposed combination strategies including targeting Wnt/β-catenin signaling pathways and combining CAF inhibitors with conventional chemotherapy to overcome treatment resistance [52]. Current challenges include CAF heterogeneity, the need for patient selection strategies based on FAP expression levels, and optimization of combination therapies with immune checkpoint inhibitors. Future directions emphasize developing next-generation FAP-targeted radiopharmaceuticals with improved tumor uptake and well-designed randomized controlled trials to establish clinical efficacy in larger populations Nature [56].

Discussions

Colorectal cancer (CRC) exhibits substantial biological and clinical heterogeneity, and current classification systems incompletely reflect the complexity of tumor–stromal interactions. Cancer-associated fibroblasts (CAFs) represent a key stromal population influencing tumor progression, immune evasion, angiogenesis, and therapeutic resistance. However, the clinical translation of CAF-targeted therapies remains limited due to subtype diversity, lack of robust biomarkers, and CAF plasticity under therapeutic pressure. Future progress will require integrating stromal biology into CRC classification frameworks and developing strategies that selectively modulate pathogenic CAF programs. Combining CAF-directed interventions with immunotherapy or chemotherapy may enable more durable responses and advance precision treatment approaches for CRC

Conclusions

Cancer-associated fibroblasts (CAFs) are critical regulators of colorectal cancer (CRC) progression and contribute to key malignant processes, including tumor growth, metabolic adaptation, immune evasion, angiogenesis, and therapeutic resistance. Recent development of CAF-directed treatment strategies—such as FAP-targeted antibodies, antibody–drug conjugates, small-molecule inhibitors, and radionuclide-based approaches—reflects growing interest in modulating the tumor microenvironment to improve therapeutic response. However, early clinical outcomes remain modest, largely due to extensive CAF heterogeneity, subtype-specific biology, and dynamic phenotypic plasticity that enables adaptive resistance. To advance CAF-targeted therapy, future efforts must focus on identifying reliable biomarkers, defining pathogenic CAF subpopulations, and integrating stromal-directed approaches with established treatment modalities including immunotherapy, chemotherapy, and metabolic inhibitors. A deeper mechanistic and spatial understanding of CAF evolution and functional programs will be essential for translating stromal targeting into precision medicine and improving outcomes for patients with CRC.

Conflict of Interest

The authors confirm that no competing interests exist and that all authors have reviewed and approved the manuscript for publication.

Author Contributions

The contributions of each author to this study are summarized as follows. SJJ, CWY, SHP, SW and SHK conceptualized and designed the overall research framework. Data curation was conducted by SJJ, CWY and SHP, while SJJ and CWY were responsible for formal data analysis. Funding for the study was acquired by WS and SHK. The experimental investigation was carried out by WS and SHK. Methodological design and refinement were performed collaboratively by SJJ, CWY and SHP. Validation and visualization of the results were undertaken by SJJ, CWY, SHP, and SHK. The original draft of the manuscript was written by CWY, and WS, and the final version of the manuscript was reviewed and edited by SJJ, CWY, WS, and SHK. All authors approved the final version.

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