解码癌症相关成纤维细胞的可塑性:胃癌进展和治疗耐药的机制见解和精确靶向策略。

IF 5.6 1区 生物学 Q2 CELL BIOLOGY
Shiyang Deng, Yong zhen Chen, Jiang Du
{"title":"解码癌症相关成纤维细胞的可塑性:胃癌进展和治疗耐药的机制见解和精确靶向策略。","authors":"Shiyang Deng,&nbsp;Yong zhen Chen,&nbsp;Jiang Du","doi":"10.1111/cpr.70094","DOIUrl":null,"url":null,"abstract":"<p>Gastric cancer (GC), the fourth leading cause of global cancer mortality, remains clinically problematic despite advances in multimodal treatments including surgery, chemotherapy, and immunotherapy. The consistently poor outcome in advanced stages needs new treatment approaches. Cancer-associated fibroblasts (CAFs) have emerged as important regulators of gastric tumour growth by dynamic interactions inside the tumour microenvironment (TME). These heterogeneous stromal elements, which are produced from several precursors, show continuous phenotypic evolution during carcinogenesis. CAFs mediate tumour-stroma crosstalk by extracellular matrix remodelling, paracrine signalling via growth factors/cytokines, and extracellular vesicle communication. Notably, CAFs and malignant cells show therapeutic pressure-driven co-evolution, and CAF-derived IL-6/IL-8 activate STAT3/NF-κB pathways to promote metabolic reprogramming while also creating drug-resistant ECM barriers. We aim to provide a transformative framework for understanding CAFs biology in gastric oncology, analysing molecular mechanisms of invasion, explaining tumour-CAF co-evolution dynamics, and mapping resistance-related regulatory networks.</p><p>Cancer-associated fibroblasts (CAFs) originate from diverse cellular precursors within the tumour microenvironment, including activated fibroblasts, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), mesenchymal/haematopoietic stem cells [<span>1</span>], adipocytes, pericytes, and stellate cells. Their transformation is governed by growth factors (e.g., TGF-β, PDGF, FGF, HGF), inflammatory cytokines (e.g., TNF, IL-6), and genetic alterations such as RAS/Myc oncogenic mutations or p53/PTEN tumour suppressor inactivation. CAFs heterogeneity stems from their multipotent origins, reflected in divergent surface markers and functional profiles. Single-cell analyses have resolved six functionally distinct CAF subclasses: three dominant subtypes—myofibroblastic (CAF-myo), inflammatory (CAF-infla), and adipose-derived (CAF-adi)—and three minor subsets including endothelial-mesenchymal transition (CAF-EndMT), peripheral nerve-like (CAF-PN), and antigen-presenting (CAF-ap) variants. Functionally, CAF subpopulations differentially regulate tumour progression through cancer cell proliferation, angiogenesis, ECM remodelling, and immunosuppression [<span>2</span>] (Table 1).</p><p>The extracellular matrix (ECM) is a complex network structure maintained in a dynamic equilibrium, primarily composed of proteins, polysaccharides, and hydrated gels. CAFs contribute to the remodelling of the tumour microenvironment at multiple levels, including the regulation of ECM stiffness, synthesis of matrix proteins, and degradation of ECM components, through the secretion of various biologically active molecules, thereby promoting the invasive process of tumour cells. Research has shown that CAFs upregulate the expression of HAPLN1 through the TGF-β1/Smad2/3 signalling pathway to regulate the stiffness level of ECM, change the biomechanical properties of ECM [<span>3</span>], create an invasive pathway for gastric cancer cells, and reduce the physical barrier, thus significantly enhancing its invasive potential. Emerging evidence confirms that cancer-associated fibroblasts (CAFs) facilitate collective tumour cell invasion through extracellular matrix (ECM) reconfiguration, creating distinct migratory trajectories. CAF-derived cytokines and matrix remodelling enzymes regulate the physical and chemical properties of the tumour microenvironment, particularly by increasing ECM stiffness to increase the invasiveness of cancer cells [<span>4</span>].</p><p>CAFs secrete TGF-β1, IL-1β, and CXCL12 to drive gastric cancer progression via SMAD/NF-κB signalling. TGF-β1 activates SMAD-dependent EMT, enhancing tumour cell migration/invasion, while IL-1β promotes proliferation through NF-κB activation. CXCL12-CXCR4 interactions inhibit apoptosis and stimulate growth. Reciprocally, gastric cancer cells reprogram CAFs: TGF-β1 induces Smad2-mediated CAFs differentiation from BMSCs, while NF-κB-driven INHBB upregulation converts normal fibroblasts to CAFs. This bidirectional cytokine network perpetuates tumour-stroma crosstalk, synergistically enhancing both cancer cell aggressiveness and CAFs activation. CAFs further strengthen their interactions with gastric cancer cells by precisely altering the mechanical properties of the gastric cancer microenvironment. Specific types of collagen secreted by CAFs activate mechanoreceptors in gastric cancer cells by increasing the stiffness of the microenvironment and upregulate the expression of CTGF, which not only enhances the infiltration capacity of CAFs but also promotes the continuous secretion of collagen to form a NF-κB-PIEZO1-YAP1-CTGF positive-feedback loop. This mechanism reveals the decisive role of mechanosensitive signalling in the gastric cancer microenvironment in tumour progression. Additionally, \n <i>H. pylori</i>\n -induced inflammatory responses further enhance the synergistic interaction between gastric cancer cells and CAFs through the PIEZO1 and NF-κB signalling pathways [<span>5</span>]. The interactions between CAFs and gastric cancer cells also exhibit highly specific regulatory features. Studies have shown that interleukins (IL-6, IL-8, IL-11, etc.) derived from CAFs play a central role in gastric cancer progression, and more critically, they create a microenvironment precisely mediated by protein modifications that continuously stimulate the production of IL-6 and IL-8 by stromal cells. PKM2, which is highly expressed in the microenvironment, provides a specific positive-feedback regulatory mechanism. By mediating the acetylation modification of the P65 protein within CAFs, it maintains the continuous activation of the NF-κB signalling pathway [<span>6</span>], significantly enhancing the ability of CAFs to secrete inflammatory factors such as IL-6 and IL-8 and further promoting the proliferation and invasion of gastric cancer cells [<span>7</span>].</p><p>CAFs originate from various cell types within the tumour microenvironment (TME) and form an intricate network of interactions with multiple biological components of this environment [<span>8</span>]. Through the secretion of cytokines, chemokines, and metabolites, CAFs finely regulate the tumour immune microenvironment (TIME), which subsequently influences tumour progression. The advent of spatially resolved transcriptomics (SRT) has revolutionised our understanding of the interactions between different cells within the tumour microenvironment (TME), featuring the analysis of genome-wide gene expression while preserving spatial structure. This technology allows precise mapping of the molecular crosstalk mechanisms between CAFs and immune cells, revealing the contextually relevant signalling networks that drive tumour progression and immune evasion. Recent studies using the SRT platform have identified spatially restricted CAFs subpopulations with distinct immunomodulatory functions. For example, inflammatory CAFs (iCAFs) localised in the vicinity of CD8<sup>+</sup> T-cell-enriched regions of gastric cancer secrete CXCL12 and TGF-β, which recruit regulatory T cells (Tregs) and polarise macrophages to an immunosuppressive M2 phenotype, and ligand-receptor pairs (e.g., CXCL12-CXCR4, TGFB1- TGFBR2) as evidenced by co-localisation analysis. In contrast, myofibroblast CAFs (myCAFs) [<span>9</span>], which form the stromal barrier surrounding the tumour, up-regulate extracellular matrix (ECM) genes (e.g., COL1A1, FN1) and physically repel cytotoxic T lymphocytes (CTLs) [<span>10</span>].</p><p>Chemotherapy-induced stress promotes phenotypic plasticity and metabolic reprogramming in CAFs, characterised by altered expression of enzymes like HK2 and LDHA. This remodelling fuels tumour growth via lactate secretion and activates downstream signalling through metabolic-epigenetic pathways. Metabolomic studies reveal that CAF-derived lactate upregulates P-glycoprotein through HIF-1α activation, establishing drug-resistant phenotypes [<span>11</span>]. The metabolic-epigenetic axis facilitates energy transfer to malignant cells while stabilising chemoresistance mechanisms, creating a microenvironment conducive to treatment evasionAt the level of metabolic reprogramming, a highly complex metabolic interaction network is constructed between CAFs and gastric cancer cells. This metabolic network transcends a simple pattern of single metabolite exchange and forms a systematic metabolic-signal transduction-epigenetic regulation axis. Specifically, highly activated CAFs generate large amounts of lactate through the glycolytic pathway, which not only serves as a preferred energetic substrate for drug-resistant gastric cancer cells to meet their ATP demand but also promotes the expression of PD-L1 through a dual mechanism: lactate directly up-regulates PD-L1 transcription by activating the NF-κB pathway and induces modification of the PD-L1 promoter through histone lactate modification [<span>12</span>], remodelling the chromatin structure to form an epigenetically activated state. Further analysis confirmed that this metabolic-epigenetic regulatory axis enhances the level of H3K27ac modification in the P-glycoprotein promoter region by recruiting the CBP/p300 acetyltransferase complex in a HIF-1α-dependent manner, thereby promoting MDR1 gene expression and maintaining a stable drug-resistant phenotype [<span>13</span>].</p><p>Recent studies have systematically revealed that resistant clones of chemotherapy residues are preferentially localised in regions with high stromal stiffness (&gt; 15 kPa). In these regions, Collagen I, upregulated by ECM remodelling, specifically binds to the DDR2 receptor, activating the NF-κB signalling pathway and inducing upregulation of PD-L1 expression. CAFs in this region show high expression of TGF-β and VEGF-A, thereby constructing a unique local immunosuppressive microenvironment [<span>14</span>]. This microenvironment heterogeneity exhibits more pronounced features in residual tumours after chemotherapy, suggesting that it may play a key role in the selective amplification of drug-resistant clones. Tumour stem cells (CSCs), central drivers of chemoresistance and relapse in gastric cancer, are finely regulated by CAFs, which maintain the CSC population and promote the transformation of non-stem cells into CSCs through the construction of a multilayered molecular network, a process closely linked to the formation of chemoresistance. CAFs regulate the CSC population through multiple mechanisms [<span>1</span>], including ligand-receptor interactions, signalling cascades, and epigenetic modifications. At the level of the signalling network, neuromodulatory protein 1 (NRG1) secreted by CAFs plays a key role in maintaining the properties of CSCs. In-depth studies have shown that NRG1 activates the downstream PI3K/AKT and IKK/NF-κB signalling pathways by binding to ErbB3/ErbB4 heterodimeric receptors on the surface of CSCs. Activated NF-κB not only directly binds to the promoter and enhancer regions of core stemness genes such as Oct4, Sox2, and Nanog, but also alters the chromatin accessibility of these regions by recruiting the SWI/SNF chromatin remodelling complex. Remarkably, under long-term chemotherapeutic pressure [<span>7</span>], this epigenetic reprogramming exhibits significant temporal specificity, undergoing a dynamic process from transient activation to stable expression, ultimately resulting in a stable mechanism for maintaining the stemness phenotype [<span>15</span>].</p><p>Research has revealed that CAFs mediate immunotherapy resistance through multiple mechanisms, including ECM remodelling, metabolic network regulation, and immunosuppressive microenvironment formation. Regarding ECM remodelling, CAFs positioned at the tumour-infiltrating front exhibit high CXCL12, TGF-β, and CCL2 expression, forming an “immune-repellent” microenvironment that blocks effector T-cell infiltration into the tumour core. Metabolically, CAFs enhance glycolysis in tumour cells via LOX and the TGFβ/IGF1 pathway, and lactate accumulation upregulates PD-L1 and enhances STAT3 activity [<span>16</span>], promoting immunosuppression. CAFs also induce arginine depletion, inhibiting T cells and promoting Treg differentiation. CAF-derived exosomes enriched in KDM5B reduce tumour cell immunogenicity through epigenetic modifications. Inhibiting ESCRT function reduces KDM5B secretion, enhancing immunotherapy efficacy. Additionally, TGF-β signalling in CAFs modulates the expression of immunosuppressive genes, maintaining the immunosuppressive microenvironment. These findings highlight the multifaceted role of CAFs in immunotherapy resistance [<span>17</span>] (Figure 1).</p><p>CAFs are a crucial component of the tumour microenvironment in GC, influencing tumour invasiveness and drug resistance through secreted factors and signalling pathways. Specifically, They secrete cytokines like IL-6, IL-8, TGF-β1, and CXCL12, driving GC cell invasion and metastasis. Therefore, targeting these pathways to reconfigure the tumour microenvironment and boost chemosensitivity offers promising therapeutic approaches [<span>18</span>]. For instance, IL-6 activates the JAK1-STAT3 pathway in GC cells, contributing to chemoresistance. In this regard, tocilizumab, an IL-6R monoclonal antibody, effectively blocks IL-6 signalling, promoting cancer cell apoptosis. Similarly, vitamin D reverses IL-8-mediated oxaliplatin resistance by inhibiting the PI3K/Akt pathway and is significantly linked to lower cancer risk and improved prognosis. Moreover, TGF-β1 induces CAFs to secrete IGFBP7, promoting tumour-associated macrophage polarisation and GC metastasis. In response, trinilast, an anti-fibrotic agent, suppresses fibroblast proliferation by inhibiting TGF-β1 signalling, reducing GC cell invasiveness. Additionally, CXCR4 antagonists like AMD3100 and motixafortide (CL-8040) inhibit the CXCL12-CXCR4 axis, suppressing GC cell invasion and metastasis. Furthermore, microRNAs (miRNAs) also play a pivotal role in GC progression. Targeting specific miRNAs, such as miR-149, can inhibit GC cell invasion and metastasis. Lastly, tumour vascularization is a critical process that facilitates the re-establishment of nutrient supply, thereby supporting tumour progression. Consequently, anti-angiogenic therapies targeting VEGF, such as ramucirumab, have shown significant efficacy in clinical trials. Cancer immunotherapy targeting CAFs markers like FAP, α-smooth muscle actin (α-SMA), and platelet-derived growth factor receptor (PDGFR) can deplete CAFs and enhance anti-tumour immunity. FAP-directed therapies enhance anti-cancer immune responses. Low-immunogenic FAP-CAR T cells (UCAR-T cells) and vaccines like SynCon FAP has effectively depleted CAFs, mitigated tumour infiltration, and enhanced T cell immunity. Gene editing technology offers a solution to effectively target CAFs and gastric cancer cells while minimising damage to normal cells [<span>19</span>]. Oncolytic adenovirus-based gene therapy (e.g., OBP-702) and low-immunogenic FAP-CAR-T cells effectively reduce CAF populations and tumour burden. Smart CAR-T cells targeting both FAP+ CAFs and tumour-associated antigens limit off-target effects. Simultaneously, nanotechnology advancements have revolutionised drug delivery strategies targeting CAFs. Liposomes and nanoparticles (NPs) can precisely target CAFs, inhibiting their bioactivity. Gold nanoparticles (GNPs) enhance targeted drug release precision, promoting the transition of CAFs from the activated to the resting state. Building upon these approaches, innovative therapeutic strategies targeting CAFs hold great promise for improving gastric cancer treatment [<span>20</span>].</p><p>CAFs are a core component of TME in gastric cancer, influencing invasion, metastasis, and drug resistance. We systematically elucidated the key mechanisms of CAFs in gastric cancer progression from multiple perspectives, including metabolic reprogramming, extracellular matrix remodelling, epigenetic regulation, spatiotemporal dynamics, and pro-cancer and drug-resistant signalling pathways between CAFs, gastric cancer cells, tumour stem cells, and immune cells. The heterogeneity of CAFs and dynamic interactions with cancer cells pose challenges but also offer opportunities for new therapies. Advanced technologies like single-cell sequencing and spatial transcriptomics have deepened the understanding of CAF markers and their dynamic changes, offering new possibilities for precise therapeutic targets. Additionally, elucidating the molecular mechanisms of CAF-gastric cancer cell interactions, especially their role in therapeutic resistance, will be a key future research direction. Innovative strategies, including gene editing and nanotechnology, show promise in preclinical studies, though clinical translation remains challenging. Future research will focus on elucidating CAF-cancer cell interactions and optimising therapeutic approaches.</p><p>Shiyang Deng, Yong zhen Chen, and Jiang Du designed and wrote the manuscript.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":"58 9","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cpr.70094","citationCount":"0","resultStr":"{\"title\":\"Decoding the Plasticity of Cancer-Associated Fibroblasts: Mechanistic Insights and Precision Targeting Strategies in Gastric Cancer Progression and Therapeutic Resistance\",\"authors\":\"Shiyang Deng,&nbsp;Yong zhen Chen,&nbsp;Jiang Du\",\"doi\":\"10.1111/cpr.70094\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Gastric cancer (GC), the fourth leading cause of global cancer mortality, remains clinically problematic despite advances in multimodal treatments including surgery, chemotherapy, and immunotherapy. The consistently poor outcome in advanced stages needs new treatment approaches. Cancer-associated fibroblasts (CAFs) have emerged as important regulators of gastric tumour growth by dynamic interactions inside the tumour microenvironment (TME). These heterogeneous stromal elements, which are produced from several precursors, show continuous phenotypic evolution during carcinogenesis. CAFs mediate tumour-stroma crosstalk by extracellular matrix remodelling, paracrine signalling via growth factors/cytokines, and extracellular vesicle communication. Notably, CAFs and malignant cells show therapeutic pressure-driven co-evolution, and CAF-derived IL-6/IL-8 activate STAT3/NF-κB pathways to promote metabolic reprogramming while also creating drug-resistant ECM barriers. We aim to provide a transformative framework for understanding CAFs biology in gastric oncology, analysing molecular mechanisms of invasion, explaining tumour-CAF co-evolution dynamics, and mapping resistance-related regulatory networks.</p><p>Cancer-associated fibroblasts (CAFs) originate from diverse cellular precursors within the tumour microenvironment, including activated fibroblasts, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), mesenchymal/haematopoietic stem cells [<span>1</span>], adipocytes, pericytes, and stellate cells. Their transformation is governed by growth factors (e.g., TGF-β, PDGF, FGF, HGF), inflammatory cytokines (e.g., TNF, IL-6), and genetic alterations such as RAS/Myc oncogenic mutations or p53/PTEN tumour suppressor inactivation. CAFs heterogeneity stems from their multipotent origins, reflected in divergent surface markers and functional profiles. Single-cell analyses have resolved six functionally distinct CAF subclasses: three dominant subtypes—myofibroblastic (CAF-myo), inflammatory (CAF-infla), and adipose-derived (CAF-adi)—and three minor subsets including endothelial-mesenchymal transition (CAF-EndMT), peripheral nerve-like (CAF-PN), and antigen-presenting (CAF-ap) variants. Functionally, CAF subpopulations differentially regulate tumour progression through cancer cell proliferation, angiogenesis, ECM remodelling, and immunosuppression [<span>2</span>] (Table 1).</p><p>The extracellular matrix (ECM) is a complex network structure maintained in a dynamic equilibrium, primarily composed of proteins, polysaccharides, and hydrated gels. CAFs contribute to the remodelling of the tumour microenvironment at multiple levels, including the regulation of ECM stiffness, synthesis of matrix proteins, and degradation of ECM components, through the secretion of various biologically active molecules, thereby promoting the invasive process of tumour cells. Research has shown that CAFs upregulate the expression of HAPLN1 through the TGF-β1/Smad2/3 signalling pathway to regulate the stiffness level of ECM, change the biomechanical properties of ECM [<span>3</span>], create an invasive pathway for gastric cancer cells, and reduce the physical barrier, thus significantly enhancing its invasive potential. Emerging evidence confirms that cancer-associated fibroblasts (CAFs) facilitate collective tumour cell invasion through extracellular matrix (ECM) reconfiguration, creating distinct migratory trajectories. CAF-derived cytokines and matrix remodelling enzymes regulate the physical and chemical properties of the tumour microenvironment, particularly by increasing ECM stiffness to increase the invasiveness of cancer cells [<span>4</span>].</p><p>CAFs secrete TGF-β1, IL-1β, and CXCL12 to drive gastric cancer progression via SMAD/NF-κB signalling. TGF-β1 activates SMAD-dependent EMT, enhancing tumour cell migration/invasion, while IL-1β promotes proliferation through NF-κB activation. CXCL12-CXCR4 interactions inhibit apoptosis and stimulate growth. Reciprocally, gastric cancer cells reprogram CAFs: TGF-β1 induces Smad2-mediated CAFs differentiation from BMSCs, while NF-κB-driven INHBB upregulation converts normal fibroblasts to CAFs. This bidirectional cytokine network perpetuates tumour-stroma crosstalk, synergistically enhancing both cancer cell aggressiveness and CAFs activation. CAFs further strengthen their interactions with gastric cancer cells by precisely altering the mechanical properties of the gastric cancer microenvironment. Specific types of collagen secreted by CAFs activate mechanoreceptors in gastric cancer cells by increasing the stiffness of the microenvironment and upregulate the expression of CTGF, which not only enhances the infiltration capacity of CAFs but also promotes the continuous secretion of collagen to form a NF-κB-PIEZO1-YAP1-CTGF positive-feedback loop. This mechanism reveals the decisive role of mechanosensitive signalling in the gastric cancer microenvironment in tumour progression. Additionally, \\n <i>H. pylori</i>\\n -induced inflammatory responses further enhance the synergistic interaction between gastric cancer cells and CAFs through the PIEZO1 and NF-κB signalling pathways [<span>5</span>]. The interactions between CAFs and gastric cancer cells also exhibit highly specific regulatory features. Studies have shown that interleukins (IL-6, IL-8, IL-11, etc.) derived from CAFs play a central role in gastric cancer progression, and more critically, they create a microenvironment precisely mediated by protein modifications that continuously stimulate the production of IL-6 and IL-8 by stromal cells. PKM2, which is highly expressed in the microenvironment, provides a specific positive-feedback regulatory mechanism. By mediating the acetylation modification of the P65 protein within CAFs, it maintains the continuous activation of the NF-κB signalling pathway [<span>6</span>], significantly enhancing the ability of CAFs to secrete inflammatory factors such as IL-6 and IL-8 and further promoting the proliferation and invasion of gastric cancer cells [<span>7</span>].</p><p>CAFs originate from various cell types within the tumour microenvironment (TME) and form an intricate network of interactions with multiple biological components of this environment [<span>8</span>]. Through the secretion of cytokines, chemokines, and metabolites, CAFs finely regulate the tumour immune microenvironment (TIME), which subsequently influences tumour progression. The advent of spatially resolved transcriptomics (SRT) has revolutionised our understanding of the interactions between different cells within the tumour microenvironment (TME), featuring the analysis of genome-wide gene expression while preserving spatial structure. This technology allows precise mapping of the molecular crosstalk mechanisms between CAFs and immune cells, revealing the contextually relevant signalling networks that drive tumour progression and immune evasion. Recent studies using the SRT platform have identified spatially restricted CAFs subpopulations with distinct immunomodulatory functions. For example, inflammatory CAFs (iCAFs) localised in the vicinity of CD8<sup>+</sup> T-cell-enriched regions of gastric cancer secrete CXCL12 and TGF-β, which recruit regulatory T cells (Tregs) and polarise macrophages to an immunosuppressive M2 phenotype, and ligand-receptor pairs (e.g., CXCL12-CXCR4, TGFB1- TGFBR2) as evidenced by co-localisation analysis. In contrast, myofibroblast CAFs (myCAFs) [<span>9</span>], which form the stromal barrier surrounding the tumour, up-regulate extracellular matrix (ECM) genes (e.g., COL1A1, FN1) and physically repel cytotoxic T lymphocytes (CTLs) [<span>10</span>].</p><p>Chemotherapy-induced stress promotes phenotypic plasticity and metabolic reprogramming in CAFs, characterised by altered expression of enzymes like HK2 and LDHA. This remodelling fuels tumour growth via lactate secretion and activates downstream signalling through metabolic-epigenetic pathways. Metabolomic studies reveal that CAF-derived lactate upregulates P-glycoprotein through HIF-1α activation, establishing drug-resistant phenotypes [<span>11</span>]. The metabolic-epigenetic axis facilitates energy transfer to malignant cells while stabilising chemoresistance mechanisms, creating a microenvironment conducive to treatment evasionAt the level of metabolic reprogramming, a highly complex metabolic interaction network is constructed between CAFs and gastric cancer cells. This metabolic network transcends a simple pattern of single metabolite exchange and forms a systematic metabolic-signal transduction-epigenetic regulation axis. Specifically, highly activated CAFs generate large amounts of lactate through the glycolytic pathway, which not only serves as a preferred energetic substrate for drug-resistant gastric cancer cells to meet their ATP demand but also promotes the expression of PD-L1 through a dual mechanism: lactate directly up-regulates PD-L1 transcription by activating the NF-κB pathway and induces modification of the PD-L1 promoter through histone lactate modification [<span>12</span>], remodelling the chromatin structure to form an epigenetically activated state. Further analysis confirmed that this metabolic-epigenetic regulatory axis enhances the level of H3K27ac modification in the P-glycoprotein promoter region by recruiting the CBP/p300 acetyltransferase complex in a HIF-1α-dependent manner, thereby promoting MDR1 gene expression and maintaining a stable drug-resistant phenotype [<span>13</span>].</p><p>Recent studies have systematically revealed that resistant clones of chemotherapy residues are preferentially localised in regions with high stromal stiffness (&gt; 15 kPa). In these regions, Collagen I, upregulated by ECM remodelling, specifically binds to the DDR2 receptor, activating the NF-κB signalling pathway and inducing upregulation of PD-L1 expression. CAFs in this region show high expression of TGF-β and VEGF-A, thereby constructing a unique local immunosuppressive microenvironment [<span>14</span>]. This microenvironment heterogeneity exhibits more pronounced features in residual tumours after chemotherapy, suggesting that it may play a key role in the selective amplification of drug-resistant clones. Tumour stem cells (CSCs), central drivers of chemoresistance and relapse in gastric cancer, are finely regulated by CAFs, which maintain the CSC population and promote the transformation of non-stem cells into CSCs through the construction of a multilayered molecular network, a process closely linked to the formation of chemoresistance. CAFs regulate the CSC population through multiple mechanisms [<span>1</span>], including ligand-receptor interactions, signalling cascades, and epigenetic modifications. At the level of the signalling network, neuromodulatory protein 1 (NRG1) secreted by CAFs plays a key role in maintaining the properties of CSCs. In-depth studies have shown that NRG1 activates the downstream PI3K/AKT and IKK/NF-κB signalling pathways by binding to ErbB3/ErbB4 heterodimeric receptors on the surface of CSCs. Activated NF-κB not only directly binds to the promoter and enhancer regions of core stemness genes such as Oct4, Sox2, and Nanog, but also alters the chromatin accessibility of these regions by recruiting the SWI/SNF chromatin remodelling complex. Remarkably, under long-term chemotherapeutic pressure [<span>7</span>], this epigenetic reprogramming exhibits significant temporal specificity, undergoing a dynamic process from transient activation to stable expression, ultimately resulting in a stable mechanism for maintaining the stemness phenotype [<span>15</span>].</p><p>Research has revealed that CAFs mediate immunotherapy resistance through multiple mechanisms, including ECM remodelling, metabolic network regulation, and immunosuppressive microenvironment formation. Regarding ECM remodelling, CAFs positioned at the tumour-infiltrating front exhibit high CXCL12, TGF-β, and CCL2 expression, forming an “immune-repellent” microenvironment that blocks effector T-cell infiltration into the tumour core. Metabolically, CAFs enhance glycolysis in tumour cells via LOX and the TGFβ/IGF1 pathway, and lactate accumulation upregulates PD-L1 and enhances STAT3 activity [<span>16</span>], promoting immunosuppression. CAFs also induce arginine depletion, inhibiting T cells and promoting Treg differentiation. CAF-derived exosomes enriched in KDM5B reduce tumour cell immunogenicity through epigenetic modifications. Inhibiting ESCRT function reduces KDM5B secretion, enhancing immunotherapy efficacy. Additionally, TGF-β signalling in CAFs modulates the expression of immunosuppressive genes, maintaining the immunosuppressive microenvironment. These findings highlight the multifaceted role of CAFs in immunotherapy resistance [<span>17</span>] (Figure 1).</p><p>CAFs are a crucial component of the tumour microenvironment in GC, influencing tumour invasiveness and drug resistance through secreted factors and signalling pathways. Specifically, They secrete cytokines like IL-6, IL-8, TGF-β1, and CXCL12, driving GC cell invasion and metastasis. Therefore, targeting these pathways to reconfigure the tumour microenvironment and boost chemosensitivity offers promising therapeutic approaches [<span>18</span>]. For instance, IL-6 activates the JAK1-STAT3 pathway in GC cells, contributing to chemoresistance. In this regard, tocilizumab, an IL-6R monoclonal antibody, effectively blocks IL-6 signalling, promoting cancer cell apoptosis. Similarly, vitamin D reverses IL-8-mediated oxaliplatin resistance by inhibiting the PI3K/Akt pathway and is significantly linked to lower cancer risk and improved prognosis. Moreover, TGF-β1 induces CAFs to secrete IGFBP7, promoting tumour-associated macrophage polarisation and GC metastasis. In response, trinilast, an anti-fibrotic agent, suppresses fibroblast proliferation by inhibiting TGF-β1 signalling, reducing GC cell invasiveness. Additionally, CXCR4 antagonists like AMD3100 and motixafortide (CL-8040) inhibit the CXCL12-CXCR4 axis, suppressing GC cell invasion and metastasis. Furthermore, microRNAs (miRNAs) also play a pivotal role in GC progression. Targeting specific miRNAs, such as miR-149, can inhibit GC cell invasion and metastasis. Lastly, tumour vascularization is a critical process that facilitates the re-establishment of nutrient supply, thereby supporting tumour progression. Consequently, anti-angiogenic therapies targeting VEGF, such as ramucirumab, have shown significant efficacy in clinical trials. Cancer immunotherapy targeting CAFs markers like FAP, α-smooth muscle actin (α-SMA), and platelet-derived growth factor receptor (PDGFR) can deplete CAFs and enhance anti-tumour immunity. FAP-directed therapies enhance anti-cancer immune responses. Low-immunogenic FAP-CAR T cells (UCAR-T cells) and vaccines like SynCon FAP has effectively depleted CAFs, mitigated tumour infiltration, and enhanced T cell immunity. Gene editing technology offers a solution to effectively target CAFs and gastric cancer cells while minimising damage to normal cells [<span>19</span>]. Oncolytic adenovirus-based gene therapy (e.g., OBP-702) and low-immunogenic FAP-CAR-T cells effectively reduce CAF populations and tumour burden. Smart CAR-T cells targeting both FAP+ CAFs and tumour-associated antigens limit off-target effects. Simultaneously, nanotechnology advancements have revolutionised drug delivery strategies targeting CAFs. Liposomes and nanoparticles (NPs) can precisely target CAFs, inhibiting their bioactivity. Gold nanoparticles (GNPs) enhance targeted drug release precision, promoting the transition of CAFs from the activated to the resting state. Building upon these approaches, innovative therapeutic strategies targeting CAFs hold great promise for improving gastric cancer treatment [<span>20</span>].</p><p>CAFs are a core component of TME in gastric cancer, influencing invasion, metastasis, and drug resistance. We systematically elucidated the key mechanisms of CAFs in gastric cancer progression from multiple perspectives, including metabolic reprogramming, extracellular matrix remodelling, epigenetic regulation, spatiotemporal dynamics, and pro-cancer and drug-resistant signalling pathways between CAFs, gastric cancer cells, tumour stem cells, and immune cells. The heterogeneity of CAFs and dynamic interactions with cancer cells pose challenges but also offer opportunities for new therapies. Advanced technologies like single-cell sequencing and spatial transcriptomics have deepened the understanding of CAF markers and their dynamic changes, offering new possibilities for precise therapeutic targets. Additionally, elucidating the molecular mechanisms of CAF-gastric cancer cell interactions, especially their role in therapeutic resistance, will be a key future research direction. Innovative strategies, including gene editing and nanotechnology, show promise in preclinical studies, though clinical translation remains challenging. Future research will focus on elucidating CAF-cancer cell interactions and optimising therapeutic approaches.</p><p>Shiyang Deng, Yong zhen Chen, and Jiang Du designed and wrote the manuscript.</p><p>The authors declare no conflicts of interest.</p>\",\"PeriodicalId\":9760,\"journal\":{\"name\":\"Cell Proliferation\",\"volume\":\"58 9\",\"pages\":\"\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cpr.70094\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Proliferation\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cpr.70094\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Proliferation","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cpr.70094","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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摘要

胃癌(GC)是全球癌症死亡的第四大原因,尽管在包括手术、化疗和免疫治疗在内的多模式治疗方面取得了进展,但在临床上仍然存在问题。晚期患者预后一直不佳,需要新的治疗方法。癌症相关成纤维细胞(CAFs)通过肿瘤微环境(TME)内的动态相互作用成为胃肿瘤生长的重要调节因子。这些异质间质因子由几种前体产生,在癌变过程中表现出连续的表型进化。CAFs通过细胞外基质重塑、生长因子/细胞因子的旁分泌信号和细胞外囊泡通讯介导肿瘤-间质串扰。值得注意的是,CAFs和恶性细胞表现出治疗压力驱动的共同进化,CAFs衍生的IL-6/IL-8激活STAT3/NF-κB通路,促进代谢重编程,同时也产生耐药的ECM屏障。我们的目标是为理解胃肿瘤中的caf生物学、分析入侵的分子机制、解释肿瘤- caf共同进化动力学以及绘制耐药性相关调控网络提供一个变动性框架。癌症相关成纤维细胞(CAFs)起源于肿瘤微环境中的多种细胞前体,包括活化的成纤维细胞、内皮细胞、上皮-间充质转化(EMT)的上皮细胞、间充质/造血干细胞[1]、脂肪细胞、周细胞和星状细胞。它们的转化受生长因子(如TGF-β、PDGF、FGF、HGF)、炎症因子(如TNF、IL-6)和基因改变(如RAS/Myc致癌突变或p53/PTEN肿瘤抑制因子失活)的控制。caf的异质性源于其多能性起源,反映在不同的表面标记和功能谱上。单细胞分析已经确定了六种功能不同的CAF亚类:三种主要亚型-肌成纤维细胞(cafo -myo),炎症(cafa -infla)和脂肪源性(cafa -adi)和三种次要亚型,包括内皮-间质转化(caft - endmt),外周神经样(cafn - pn)和抗原呈递(cafa -ap)变体。功能上,CAF亚群通过癌细胞增殖、血管生成、ECM重塑和免疫抑制[2]对肿瘤进展进行差异调节(表1)。细胞外基质(ECM)是一个保持动态平衡的复杂网络结构,主要由蛋白质、多糖和水合凝胶组成。CAFs通过分泌各种生物活性分子,在多个层面上促进肿瘤微环境的重塑,包括调节ECM刚度、合成基质蛋白和降解ECM成分,从而促进肿瘤细胞的侵袭过程。研究表明,CAFs通过TGF-β1/Smad2/3信号通路上调HAPLN1的表达,调节ECM的刚度水平,改变ECM[3]的生物力学特性,为胃癌细胞创造侵袭通路,降低物理屏障,显著增强其侵袭潜力。新出现的证据证实,癌症相关成纤维细胞(CAFs)通过细胞外基质(ECM)重构促进肿瘤细胞的集体侵袭,形成独特的迁移轨迹。cafa衍生的细胞因子和基质重塑酶调节肿瘤微环境的物理和化学特性,特别是通过增加ECM硬度来增加癌细胞的侵袭性。CAFs分泌TGF-β1、IL-1β和CXCL12,通过SMAD/NF-κB信号传导驱动胃癌进展。TGF-β1激活smad依赖性EMT,增强肿瘤细胞迁移/侵袭,而IL-1β通过活化NF-κB促进肿瘤细胞增殖。CXCL12-CXCR4相互作用抑制细胞凋亡并刺激生长。反过来,胃癌细胞重编程CAFs: TGF-β1诱导smad2介导的CAFs从BMSCs分化,而NF-κ b驱动的INHBB上调将正常成纤维细胞转化为CAFs。这种双向细胞因子网络使肿瘤间质串扰永久化,协同增强癌细胞的侵袭性和CAFs的激活。通过精确改变胃癌微环境的力学特性,CAFs进一步加强了与胃癌细胞的相互作用。CAFs分泌的特定类型的胶原通过增加微环境的刚度,激活胃癌细胞的机械受体,上调CTGF的表达,不仅增强了CAFs的浸润能力,而且促进胶原的持续分泌,形成NF-κB-PIEZO1-YAP1-CTGF的正反馈回路。这一机制揭示了胃癌微环境中机械敏感信号在肿瘤进展中的决定性作用。另外 , H。 幽门螺杆菌诱导的炎症反应通过PIEZO1和NF-κB信号通路[5]进一步增强胃癌细胞与CAFs之间的协同相互作用。CAFs与胃癌细胞之间的相互作用也表现出高度特异性的调控特征。研究表明,来自CAFs的白细胞介素(IL-6、IL-8、IL-11等)在胃癌的进展中起着核心作用,更关键的是,它们创造了一个由蛋白质修饰精确介导的微环境,不断刺激基质细胞产生IL-6和IL-8。PKM2在微环境中高度表达,提供了一种特定的正反馈调控机制。通过介导CAFs内P65蛋白的乙酰化修饰,维持NF-κB信号通路[6]的持续激活,显著增强CAFs分泌IL-6、IL-8等炎症因子的能力,进一步促进胃癌细胞[7]的增殖和侵袭。CAFs起源于肿瘤微环境(TME)内的各种细胞类型,并与该环境的多种生物成分形成复杂的相互作用网络[8]。通过分泌细胞因子、趋化因子和代谢物,CAFs精细调节肿瘤免疫微环境(TIME),进而影响肿瘤进展。空间解析转录组学(SRT)的出现彻底改变了我们对肿瘤微环境(TME)内不同细胞之间相互作用的理解,其特点是在保留空间结构的同时分析全基因组基因表达。这项技术可以精确绘制caf和免疫细胞之间的分子串扰机制,揭示驱动肿瘤进展和免疫逃避的上下文相关信号网络。最近使用SRT平台的研究已经确定了具有不同免疫调节功能的空间限制性CAFs亚群。例如,在胃癌的CD8+ T细胞富集区附近定位的炎性CAFs (iCAFs)分泌CXCL12和TGF-β,它们募集调节性T细胞(treg)并使巨噬细胞极化为免疫抑制的M2表型,并通过共定位分析证明配体受体对(如CXCL12- cxcr4, TGFB1- TGFBR2)。相反,形成肿瘤周围基质屏障的肌成纤维细胞CAFs (myCAFs)[9]上调细胞外基质(ECM)基因(如COL1A1, FN1)并物理排斥细胞毒性T淋巴细胞(ctl)[10]。化疗诱导的应激促进了cas的表型可塑性和代谢重编程,其特征是HK2和LDHA等酶的表达改变。这种重塑通过乳酸分泌促进肿瘤生长,并通过代谢-表观遗传途径激活下游信号。代谢组学研究表明,caf衍生的乳酸通过HIF-1α激活上调p -糖蛋白,建立耐药表型[11]。代谢-表观遗传轴促进能量向恶性细胞转移,同时稳定化疗耐药机制,创造有利于逃避治疗的微环境。在代谢重编程水平上,cas与胃癌细胞之间构建了高度复杂的代谢相互作用网络。这种代谢网络超越了单一代谢物交换的简单模式,形成了一个系统的代谢-信号转导-表观遗传调控轴。具体来说,高活化的CAFs通过糖酵解途径产生大量乳酸,乳酸不仅是耐药胃癌细胞满足ATP需求的首选能量底物,而且通过双重机制促进PD-L1的表达:乳酸通过激活NF-κB通路直接上调PD-L1转录,并通过组蛋白乳酸修饰[12]诱导PD-L1启动子修饰,重塑染色质结构,形成表观遗传激活状态。进一步分析证实,该代谢-表观遗传调控轴以hif -1α-依赖性方式募集CBP/p300乙酰转移酶复合物,从而增强p -糖蛋白启动子区H3K27ac修饰水平,从而促进MDR1基因表达,维持稳定的耐药表型[13]。最近的研究系统地揭示了化疗残留物的耐药克隆优先定位于高基质刚度(15 kPa)的区域。在这些区域,ECM重塑上调的I型胶原蛋白特异性地与DDR2受体结合,激活NF-κB信号通路,诱导PD-L1表达上调。该区域的CAFs高表达TGF-β和VEGF-A,从而构建了独特的局部免疫抑制微环境[14]。 这种微环境异质性在化疗后残留肿瘤中表现出更明显的特征,表明它可能在耐药克隆的选择性扩增中发挥关键作用。肿瘤干细胞(tumor stem cells, CSCs)是胃癌化疗耐药和复发的核心驱动因素,它受到caf的精细调控,通过构建多层分子网络维持CSC群体并促进非干细胞向CSCs的转化,这一过程与化疗耐药的形成密切相关。CAFs通过多种机制调节CSC群体,包括配体-受体相互作用、信号级联和表观遗传修饰。在信号网络水平上,CAFs分泌的神经调节蛋白1 (neuromodulatory protein 1, NRG1)在维持CSCs的特性中起着关键作用。深入研究表明,NRG1通过与CSCs表面的ErbB3/ErbB4异二聚体受体结合,激活下游PI3K/AKT和IKK/NF-κB信号通路。活化的NF-κB不仅直接结合Oct4、Sox2和Nanog等核心干性基因的启动子和增强子区域,而且通过募集SWI/SNF染色质重塑复合体改变这些区域的染色质可及性。值得注意的是,在长期化疗压力[7]下,这种表观遗传重编程表现出显著的时间特异性,经历了从短暂激活到稳定表达的动态过程,最终形成了维持干性表型[15]的稳定机制。研究表明,CAFs通过多种机制介导免疫治疗耐药,包括ECM重塑、代谢网络调节和免疫抑制微环境的形成。在ECM重塑方面,位于肿瘤浸润前沿的CAFs表现出高水平的CXCL12、TGF-β和CCL2表达,形成“免疫排斥”微环境,阻止效应t细胞浸润到肿瘤核心。在代谢方面,CAFs通过LOX和TGFβ/IGF1途径增强肿瘤细胞中的糖酵解,乳酸积累上调PD-L1并增强STAT3活性[16],促进免疫抑制。CAFs还诱导精氨酸耗竭,抑制T细胞,促进Treg分化。富集KDM5B的caf衍生外泌体通过表观遗传修饰降低肿瘤细胞的免疫原性。抑制ESCRT功能可减少KDM5B分泌,增强免疫治疗效果。此外,TGF-β信号在CAFs中调节免疫抑制基因的表达,维持免疫抑制微环境。这些发现突出了CAFs在免疫治疗耐药[17]中的多方面作用(图1)。在胃癌中,CAFs是肿瘤微环境的重要组成部分,通过分泌因子和信号通路影响肿瘤的侵袭性和耐药性。具体来说,它们分泌IL-6、IL-8、TGF-β1、CXCL12等细胞因子,驱动GC细胞侵袭转移。因此,靶向这些途径来重新配置肿瘤微环境和提高化疗敏感性提供了有希望的治疗方法。例如,IL-6激活GC细胞中的JAK1-STAT3通路,促进化学耐药。在这方面,tocilizumab,一种IL-6R单克隆抗体,有效阻断IL-6信号传导,促进癌细胞凋亡。同样,维生素D通过抑制PI3K/Akt通路逆转il -8介导的奥沙利铂耐药,并与降低癌症风险和改善预后显著相关。TGF-β1诱导cas分泌IGFBP7,促进肿瘤相关巨噬细胞极化和GC转移。作为回应,抗纤维化药物trinilast通过抑制TGF-β1信号传导抑制成纤维细胞增殖,降低GC细胞的侵袭性。此外,CXCR4拮抗剂如AMD3100和motixafortide (CL-8040)抑制CXCL12-CXCR4轴,抑制GC细胞的侵袭和转移。此外,microRNAs (miRNAs)在GC的进展中也起着关键作用。靶向特定的mirna,如miR-149,可以抑制GC细胞的侵袭和转移。最后,肿瘤血管化是促进营养供应重建的关键过程,从而支持肿瘤进展。因此,针对VEGF的抗血管生成疗法,如ramucirumab,在临床试验中显示出显著的疗效。针对cas标志物如FAP、α-平滑肌肌动蛋白(α-SMA)和血小板衍生生长因子受体(PDGFR)的癌症免疫治疗可以消耗cas并增强抗肿瘤免疫。以fap为导向的治疗可增强抗癌免疫反应。低免疫原性FAP- car -T细胞(UCAR-T细胞)和像SynCon FAP这样的疫苗有效地消耗了CAFs,减轻了肿瘤浸润,增强了T细胞免疫力。基因编辑技术提供了一种有效靶向CAFs和胃癌细胞的解决方案,同时将对正常细胞的损伤降到最低。 基于溶瘤腺病毒的基因治疗(如OBP-702)和低免疫原性FAP-CAR-T细胞有效地减少CAF种群和肿瘤负担。靶向FAP+ CAFs和肿瘤相关抗原的智能CAR-T细胞限制了脱靶效应。同时,纳米技术的进步已经彻底改变了针对caf的药物递送策略。脂质体和纳米颗粒(NPs)可以精确靶向cas,抑制其生物活性。金纳米颗粒(GNPs)提高了靶向药物释放的精度,促进了CAFs从激活状态到静息状态的转变。在这些方法的基础上,针对caf的创新治疗策略有望改善胃癌的治疗。CAFs是胃癌TME的核心成分,影响胃癌的侵袭、转移和耐药。我们从代谢重编程、细胞外基质重塑、表观遗传调控、时空动力学以及CAFs与胃癌细胞、肿瘤干细胞和免疫细胞之间的促癌和耐药信号通路等多个角度系统地阐明了CAFs在胃癌进展中的关键机制。CAFs的异质性和与癌细胞的动态相互作用带来了挑战,但也为新疗法提供了机会。单细胞测序和空间转录组学等先进技术加深了对CAF标记物及其动态变化的理解,为精确的治疗靶点提供了新的可能性。此外,阐明cafa -胃癌细胞相互作用的分子机制,特别是其在治疗耐药中的作用,将是未来重要的研究方向。包括基因编辑和纳米技术在内的创新策略在临床前研究中显示出希望,尽管临床转化仍然具有挑战性。未来的研究将集中在阐明ca -癌细胞相互作用和优化治疗方法上。邓世阳、陈永真、杜江设计并撰写了手稿。作者声明无利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Decoding the Plasticity of Cancer-Associated Fibroblasts: Mechanistic Insights and Precision Targeting Strategies in Gastric Cancer Progression and Therapeutic Resistance

Decoding the Plasticity of Cancer-Associated Fibroblasts: Mechanistic Insights and Precision Targeting Strategies in Gastric Cancer Progression and Therapeutic Resistance

Gastric cancer (GC), the fourth leading cause of global cancer mortality, remains clinically problematic despite advances in multimodal treatments including surgery, chemotherapy, and immunotherapy. The consistently poor outcome in advanced stages needs new treatment approaches. Cancer-associated fibroblasts (CAFs) have emerged as important regulators of gastric tumour growth by dynamic interactions inside the tumour microenvironment (TME). These heterogeneous stromal elements, which are produced from several precursors, show continuous phenotypic evolution during carcinogenesis. CAFs mediate tumour-stroma crosstalk by extracellular matrix remodelling, paracrine signalling via growth factors/cytokines, and extracellular vesicle communication. Notably, CAFs and malignant cells show therapeutic pressure-driven co-evolution, and CAF-derived IL-6/IL-8 activate STAT3/NF-κB pathways to promote metabolic reprogramming while also creating drug-resistant ECM barriers. We aim to provide a transformative framework for understanding CAFs biology in gastric oncology, analysing molecular mechanisms of invasion, explaining tumour-CAF co-evolution dynamics, and mapping resistance-related regulatory networks.

Cancer-associated fibroblasts (CAFs) originate from diverse cellular precursors within the tumour microenvironment, including activated fibroblasts, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), mesenchymal/haematopoietic stem cells [1], adipocytes, pericytes, and stellate cells. Their transformation is governed by growth factors (e.g., TGF-β, PDGF, FGF, HGF), inflammatory cytokines (e.g., TNF, IL-6), and genetic alterations such as RAS/Myc oncogenic mutations or p53/PTEN tumour suppressor inactivation. CAFs heterogeneity stems from their multipotent origins, reflected in divergent surface markers and functional profiles. Single-cell analyses have resolved six functionally distinct CAF subclasses: three dominant subtypes—myofibroblastic (CAF-myo), inflammatory (CAF-infla), and adipose-derived (CAF-adi)—and three minor subsets including endothelial-mesenchymal transition (CAF-EndMT), peripheral nerve-like (CAF-PN), and antigen-presenting (CAF-ap) variants. Functionally, CAF subpopulations differentially regulate tumour progression through cancer cell proliferation, angiogenesis, ECM remodelling, and immunosuppression [2] (Table 1).

The extracellular matrix (ECM) is a complex network structure maintained in a dynamic equilibrium, primarily composed of proteins, polysaccharides, and hydrated gels. CAFs contribute to the remodelling of the tumour microenvironment at multiple levels, including the regulation of ECM stiffness, synthesis of matrix proteins, and degradation of ECM components, through the secretion of various biologically active molecules, thereby promoting the invasive process of tumour cells. Research has shown that CAFs upregulate the expression of HAPLN1 through the TGF-β1/Smad2/3 signalling pathway to regulate the stiffness level of ECM, change the biomechanical properties of ECM [3], create an invasive pathway for gastric cancer cells, and reduce the physical barrier, thus significantly enhancing its invasive potential. Emerging evidence confirms that cancer-associated fibroblasts (CAFs) facilitate collective tumour cell invasion through extracellular matrix (ECM) reconfiguration, creating distinct migratory trajectories. CAF-derived cytokines and matrix remodelling enzymes regulate the physical and chemical properties of the tumour microenvironment, particularly by increasing ECM stiffness to increase the invasiveness of cancer cells [4].

CAFs secrete TGF-β1, IL-1β, and CXCL12 to drive gastric cancer progression via SMAD/NF-κB signalling. TGF-β1 activates SMAD-dependent EMT, enhancing tumour cell migration/invasion, while IL-1β promotes proliferation through NF-κB activation. CXCL12-CXCR4 interactions inhibit apoptosis and stimulate growth. Reciprocally, gastric cancer cells reprogram CAFs: TGF-β1 induces Smad2-mediated CAFs differentiation from BMSCs, while NF-κB-driven INHBB upregulation converts normal fibroblasts to CAFs. This bidirectional cytokine network perpetuates tumour-stroma crosstalk, synergistically enhancing both cancer cell aggressiveness and CAFs activation. CAFs further strengthen their interactions with gastric cancer cells by precisely altering the mechanical properties of the gastric cancer microenvironment. Specific types of collagen secreted by CAFs activate mechanoreceptors in gastric cancer cells by increasing the stiffness of the microenvironment and upregulate the expression of CTGF, which not only enhances the infiltration capacity of CAFs but also promotes the continuous secretion of collagen to form a NF-κB-PIEZO1-YAP1-CTGF positive-feedback loop. This mechanism reveals the decisive role of mechanosensitive signalling in the gastric cancer microenvironment in tumour progression. Additionally, H. pylori -induced inflammatory responses further enhance the synergistic interaction between gastric cancer cells and CAFs through the PIEZO1 and NF-κB signalling pathways [5]. The interactions between CAFs and gastric cancer cells also exhibit highly specific regulatory features. Studies have shown that interleukins (IL-6, IL-8, IL-11, etc.) derived from CAFs play a central role in gastric cancer progression, and more critically, they create a microenvironment precisely mediated by protein modifications that continuously stimulate the production of IL-6 and IL-8 by stromal cells. PKM2, which is highly expressed in the microenvironment, provides a specific positive-feedback regulatory mechanism. By mediating the acetylation modification of the P65 protein within CAFs, it maintains the continuous activation of the NF-κB signalling pathway [6], significantly enhancing the ability of CAFs to secrete inflammatory factors such as IL-6 and IL-8 and further promoting the proliferation and invasion of gastric cancer cells [7].

CAFs originate from various cell types within the tumour microenvironment (TME) and form an intricate network of interactions with multiple biological components of this environment [8]. Through the secretion of cytokines, chemokines, and metabolites, CAFs finely regulate the tumour immune microenvironment (TIME), which subsequently influences tumour progression. The advent of spatially resolved transcriptomics (SRT) has revolutionised our understanding of the interactions between different cells within the tumour microenvironment (TME), featuring the analysis of genome-wide gene expression while preserving spatial structure. This technology allows precise mapping of the molecular crosstalk mechanisms between CAFs and immune cells, revealing the contextually relevant signalling networks that drive tumour progression and immune evasion. Recent studies using the SRT platform have identified spatially restricted CAFs subpopulations with distinct immunomodulatory functions. For example, inflammatory CAFs (iCAFs) localised in the vicinity of CD8+ T-cell-enriched regions of gastric cancer secrete CXCL12 and TGF-β, which recruit regulatory T cells (Tregs) and polarise macrophages to an immunosuppressive M2 phenotype, and ligand-receptor pairs (e.g., CXCL12-CXCR4, TGFB1- TGFBR2) as evidenced by co-localisation analysis. In contrast, myofibroblast CAFs (myCAFs) [9], which form the stromal barrier surrounding the tumour, up-regulate extracellular matrix (ECM) genes (e.g., COL1A1, FN1) and physically repel cytotoxic T lymphocytes (CTLs) [10].

Chemotherapy-induced stress promotes phenotypic plasticity and metabolic reprogramming in CAFs, characterised by altered expression of enzymes like HK2 and LDHA. This remodelling fuels tumour growth via lactate secretion and activates downstream signalling through metabolic-epigenetic pathways. Metabolomic studies reveal that CAF-derived lactate upregulates P-glycoprotein through HIF-1α activation, establishing drug-resistant phenotypes [11]. The metabolic-epigenetic axis facilitates energy transfer to malignant cells while stabilising chemoresistance mechanisms, creating a microenvironment conducive to treatment evasionAt the level of metabolic reprogramming, a highly complex metabolic interaction network is constructed between CAFs and gastric cancer cells. This metabolic network transcends a simple pattern of single metabolite exchange and forms a systematic metabolic-signal transduction-epigenetic regulation axis. Specifically, highly activated CAFs generate large amounts of lactate through the glycolytic pathway, which not only serves as a preferred energetic substrate for drug-resistant gastric cancer cells to meet their ATP demand but also promotes the expression of PD-L1 through a dual mechanism: lactate directly up-regulates PD-L1 transcription by activating the NF-κB pathway and induces modification of the PD-L1 promoter through histone lactate modification [12], remodelling the chromatin structure to form an epigenetically activated state. Further analysis confirmed that this metabolic-epigenetic regulatory axis enhances the level of H3K27ac modification in the P-glycoprotein promoter region by recruiting the CBP/p300 acetyltransferase complex in a HIF-1α-dependent manner, thereby promoting MDR1 gene expression and maintaining a stable drug-resistant phenotype [13].

Recent studies have systematically revealed that resistant clones of chemotherapy residues are preferentially localised in regions with high stromal stiffness (> 15 kPa). In these regions, Collagen I, upregulated by ECM remodelling, specifically binds to the DDR2 receptor, activating the NF-κB signalling pathway and inducing upregulation of PD-L1 expression. CAFs in this region show high expression of TGF-β and VEGF-A, thereby constructing a unique local immunosuppressive microenvironment [14]. This microenvironment heterogeneity exhibits more pronounced features in residual tumours after chemotherapy, suggesting that it may play a key role in the selective amplification of drug-resistant clones. Tumour stem cells (CSCs), central drivers of chemoresistance and relapse in gastric cancer, are finely regulated by CAFs, which maintain the CSC population and promote the transformation of non-stem cells into CSCs through the construction of a multilayered molecular network, a process closely linked to the formation of chemoresistance. CAFs regulate the CSC population through multiple mechanisms [1], including ligand-receptor interactions, signalling cascades, and epigenetic modifications. At the level of the signalling network, neuromodulatory protein 1 (NRG1) secreted by CAFs plays a key role in maintaining the properties of CSCs. In-depth studies have shown that NRG1 activates the downstream PI3K/AKT and IKK/NF-κB signalling pathways by binding to ErbB3/ErbB4 heterodimeric receptors on the surface of CSCs. Activated NF-κB not only directly binds to the promoter and enhancer regions of core stemness genes such as Oct4, Sox2, and Nanog, but also alters the chromatin accessibility of these regions by recruiting the SWI/SNF chromatin remodelling complex. Remarkably, under long-term chemotherapeutic pressure [7], this epigenetic reprogramming exhibits significant temporal specificity, undergoing a dynamic process from transient activation to stable expression, ultimately resulting in a stable mechanism for maintaining the stemness phenotype [15].

Research has revealed that CAFs mediate immunotherapy resistance through multiple mechanisms, including ECM remodelling, metabolic network regulation, and immunosuppressive microenvironment formation. Regarding ECM remodelling, CAFs positioned at the tumour-infiltrating front exhibit high CXCL12, TGF-β, and CCL2 expression, forming an “immune-repellent” microenvironment that blocks effector T-cell infiltration into the tumour core. Metabolically, CAFs enhance glycolysis in tumour cells via LOX and the TGFβ/IGF1 pathway, and lactate accumulation upregulates PD-L1 and enhances STAT3 activity [16], promoting immunosuppression. CAFs also induce arginine depletion, inhibiting T cells and promoting Treg differentiation. CAF-derived exosomes enriched in KDM5B reduce tumour cell immunogenicity through epigenetic modifications. Inhibiting ESCRT function reduces KDM5B secretion, enhancing immunotherapy efficacy. Additionally, TGF-β signalling in CAFs modulates the expression of immunosuppressive genes, maintaining the immunosuppressive microenvironment. These findings highlight the multifaceted role of CAFs in immunotherapy resistance [17] (Figure 1).

CAFs are a crucial component of the tumour microenvironment in GC, influencing tumour invasiveness and drug resistance through secreted factors and signalling pathways. Specifically, They secrete cytokines like IL-6, IL-8, TGF-β1, and CXCL12, driving GC cell invasion and metastasis. Therefore, targeting these pathways to reconfigure the tumour microenvironment and boost chemosensitivity offers promising therapeutic approaches [18]. For instance, IL-6 activates the JAK1-STAT3 pathway in GC cells, contributing to chemoresistance. In this regard, tocilizumab, an IL-6R monoclonal antibody, effectively blocks IL-6 signalling, promoting cancer cell apoptosis. Similarly, vitamin D reverses IL-8-mediated oxaliplatin resistance by inhibiting the PI3K/Akt pathway and is significantly linked to lower cancer risk and improved prognosis. Moreover, TGF-β1 induces CAFs to secrete IGFBP7, promoting tumour-associated macrophage polarisation and GC metastasis. In response, trinilast, an anti-fibrotic agent, suppresses fibroblast proliferation by inhibiting TGF-β1 signalling, reducing GC cell invasiveness. Additionally, CXCR4 antagonists like AMD3100 and motixafortide (CL-8040) inhibit the CXCL12-CXCR4 axis, suppressing GC cell invasion and metastasis. Furthermore, microRNAs (miRNAs) also play a pivotal role in GC progression. Targeting specific miRNAs, such as miR-149, can inhibit GC cell invasion and metastasis. Lastly, tumour vascularization is a critical process that facilitates the re-establishment of nutrient supply, thereby supporting tumour progression. Consequently, anti-angiogenic therapies targeting VEGF, such as ramucirumab, have shown significant efficacy in clinical trials. Cancer immunotherapy targeting CAFs markers like FAP, α-smooth muscle actin (α-SMA), and platelet-derived growth factor receptor (PDGFR) can deplete CAFs and enhance anti-tumour immunity. FAP-directed therapies enhance anti-cancer immune responses. Low-immunogenic FAP-CAR T cells (UCAR-T cells) and vaccines like SynCon FAP has effectively depleted CAFs, mitigated tumour infiltration, and enhanced T cell immunity. Gene editing technology offers a solution to effectively target CAFs and gastric cancer cells while minimising damage to normal cells [19]. Oncolytic adenovirus-based gene therapy (e.g., OBP-702) and low-immunogenic FAP-CAR-T cells effectively reduce CAF populations and tumour burden. Smart CAR-T cells targeting both FAP+ CAFs and tumour-associated antigens limit off-target effects. Simultaneously, nanotechnology advancements have revolutionised drug delivery strategies targeting CAFs. Liposomes and nanoparticles (NPs) can precisely target CAFs, inhibiting their bioactivity. Gold nanoparticles (GNPs) enhance targeted drug release precision, promoting the transition of CAFs from the activated to the resting state. Building upon these approaches, innovative therapeutic strategies targeting CAFs hold great promise for improving gastric cancer treatment [20].

CAFs are a core component of TME in gastric cancer, influencing invasion, metastasis, and drug resistance. We systematically elucidated the key mechanisms of CAFs in gastric cancer progression from multiple perspectives, including metabolic reprogramming, extracellular matrix remodelling, epigenetic regulation, spatiotemporal dynamics, and pro-cancer and drug-resistant signalling pathways between CAFs, gastric cancer cells, tumour stem cells, and immune cells. The heterogeneity of CAFs and dynamic interactions with cancer cells pose challenges but also offer opportunities for new therapies. Advanced technologies like single-cell sequencing and spatial transcriptomics have deepened the understanding of CAF markers and their dynamic changes, offering new possibilities for precise therapeutic targets. Additionally, elucidating the molecular mechanisms of CAF-gastric cancer cell interactions, especially their role in therapeutic resistance, will be a key future research direction. Innovative strategies, including gene editing and nanotechnology, show promise in preclinical studies, though clinical translation remains challenging. Future research will focus on elucidating CAF-cancer cell interactions and optimising therapeutic approaches.

Shiyang Deng, Yong zhen Chen, and Jiang Du designed and wrote the manuscript.

The authors declare no conflicts of interest.

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来源期刊
Cell Proliferation
Cell Proliferation 生物-细胞生物学
CiteScore
14.80
自引率
2.40%
发文量
198
审稿时长
1 months
期刊介绍: Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.
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