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Abstract

Metabolic reprogramming occurs when tumor cells replenish themselves with nutrients required for growth to meet their metabolic needs. Cancer-associated fibroblasts (CAFs) are activated fibroblasts involved in building the c (TME) to promote tumor progression and metastasis. Metabolic reprogramming of CAFs can interact with cancer cells to generate metabolic crosstalk. Furthermore, CAF metabolic reprogramming has great potential as a new field of tumor treatment. This review summarizes the role of CAFs in TME and the mechanisms by which metabolic reprogramming of CAFs causes cancer progression and metastasis, demonstrating the great potential of CAF metabolic reprogramming in cancer chemotherapy and immunotherapy treatment. Furthermore, we provide an outlook for future CAF metabolic reprogramming for cancer treatment.

Keywords

Metabolic reprogramming CAFs metastasis immunotherapy chemotherapy

Introduction

Tumor proliferation, invasion and metastasis are inseparable from the tumor microenvironment (TME). The TME is a complex ecosystem containing multiple cell types and noncellular components, including cancer cells, immune cells, endothelial cells, cancer-associated fibroblasts (CAFs), microvasculature, infiltrating biomolecules, and extracellular matrix (ECM).¹ These cells interact with cancer cells via complex communication networks (both autocrine and paracrine) in TME to induce tumor angiogenesis, immune evasion, apoptosis inhibition, drug resistance, and metabolic reprogramming.² Cancer cells can replenish nutrients required for growth by benefiting from metabolic adaptations obtained through various biomolecule synthesis, the provision of reducing equivalents, and adenosine triphosphate (ATP) production in the endocytic and extracellular pathways, tumor cells can meet the replenishment of nutrients required for growth, resulting in rapid and uncontrolled proliferation. Metabolic reprogramming refers to the process of adaptive changes in the metabolic properties of tumor cells through the conversion of available nutrients into biomass energy.³

Tumor microenvironment is where metabolic reprogramming occurs most frequently, and signaling molecules, immune cells, fibroblasts, ECM, and peripheral vasculature can regulate tumor progression through metabolic reprogramming.⁴ Activated fibroblasts, known as CAFs, constitute most stromal cells in the TME.⁵ In contrast to normal fibroblasts (NFs), CAFs are involved in remodeling TME (such as cytokine, enzyme, and microRNA [miRNA] secretion, ECM track generation, and stromal stiffness enhancement) to promote tumor progression and metastasis.⁵ Metabolic reprogramming of CAFs is defined as the reverse Warburg effect (RWE), characterized by an increase in lactate, glutamine, and pyruvate levels from aerobic glycolysis.² Metabolically reprogrammed CAFs replenish nutrients consumed by organelles (such as mitochondria) during tumor metabolism by generating energy at higher levels. In a recent study, Wu et al⁶ discovered that transforming growth factor (TGF-β) RII can inhibit glucose metabolism in CAFs by attenuating Pyruvate kinase M2 (PKM2) nuclear translocation, thereby suppressing oral cancer tumor growth, indicating that targeting CAFs may be a new approach for cancer therapy. Furthermore, although the interactions between different cells in TME have received considerable attention, the complex relationship between the metabolic reprogramming of CAFs and cancer cells remains unknown and requires further investigation.

This review describes the current understanding of metabolic reprogramming of CAFs and their crosstalk with cancer cells. We emphasize potential therapeutic opportunities for targeting CAF metabolic reprogramming and focus on targeting CAFs strategies and immune cell metabolic crosstalk in cancer immunotherapy. In addition, we predicted the future of metabolic reprogramming of CAFs in cancer treatment.

Crosstalk Between CAFs and ECM: Promoting Immunosuppressive TME Formation

Extracellular matrix is a complex network composed of different macromolecules, including glycoproteins, fibronectin, proteoglycans, and collagen, and is responsible for maintaining normal tissue integrity, homeostasis, and growth.⁷ Cancer-associated fibroblasts reshape ECM in several ways.^8-10 First, CAFs can increase ECM matrix stiffness and degrade its normal structure by producing matrix metalloproteinases (MMP) (such as MMP-1 and MMP-3) and secreting matrix proteins (such as type I collagen and fibronectin), thus reshaping ECM.⁸ Second, cytokine TGF-β1 released by CAFs enhances CAF invasiveness and stimulates ECM fibrosis by increasing smooth muscle α-actin (ACTA2), fibronectin, and laminin expression.⁹ In addition, CAFs can upregulate various cytoskeletal regulators (such as diaphanous-related formin-3 [DIAPH3] and anillin (ANLN)) expressions through yes-associated protein (YAP) activation, inducing ECM stiffening.¹¹ Therefore, CAFs mediate mechanized fibrous barrier formation by fibrotic ECM, which is the basis for immunosuppressive TME formation. With intensive research, CAF-remodeled ECM was found to promote immunosuppressive TME formation by suppressing immune cell function and recruiting immunosuppressive cells, thus creating favorable conditions for tumor invasion and metastasis (Figure 1).¹²

Cancer-associated fibroblast-remodeled ECM suppresses immune cell function. The ECM remodeled by CAFs acts as a physical barrier to inhibit the recruitment of immune cells to cancer sites by blocking immune cells (especially T cells) from cancer cells, thus impeding their participation in the immune response to TME and ultimately exerting an immunosuppressive function.¹³ Cancer-associated fibroblast-remodeled ECM limits T-cell contact with cancer cells by increasing collagen deposition around tumor cell clusters, especially CD4⁺ T and CD8⁺ T cells.¹⁴ This phenomenon, in which the infiltration of immune cells is inhibited and cannot kill tumors, is called tumor immune desertification, and how to reverse tumor immune desertification may be the key to improving the immunotherapy effectiveness.¹⁵ Similarly, CAF-remodeled ECM can lead to poor infiltration of CD8⁺ cytotoxic T cells by exploiting the fibroregulatory effects of focal adhesion kinases (FAKs), thereby suppressing the immune response.¹⁶ Furthermore, CAF-remodeled ECM leads to hypoxic TME formation by accumulating matrix proteins, inducing the soluble factor vascular endothelial-derived growth factor (VEGF) production to reduce the accumulation rate of circulating T-cells through the tumor vasculature, ultimately reducing their infiltration.¹⁷ Therefore, CAF-remodeled ECM can promote immunosuppressive microenvironment formation by suppressing immune cell functions. However, recent studies have demonstrated that CAF-remodeled ECM suppresses T-cell function. Further studies are needed to determine the suppressive effect of CAF-remodeled ECM on other immune system cell functions.

Cancer-associated fibroblast-remodeled ECM recruits immunosuppressive cells. In the TME, immunosuppressive cells indirectly block immunotherapy through secreted factors that establish immune tolerance.¹⁸ Cancer-associated fibroblast-remodeled ECM with increased collagen density recruits TAMs, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (T-regs), leading to direct exhaustion of CD8⁺ T cells by activating intracellular FAKs, thereby triggering immunosuppression.¹⁹ Cancer-associated fibroblast-remodeled ECM promotes M2-type polarization of macrophages and recruitment of tumor-associated macrophages (TAMs) by inducing oncogenic collagen matrices, thereby promoting immunosuppressive microenvironment formation.²⁰ Furthermore, fibrotic ECM alters factors affecting macrophage polarization in TME with the assistance of hyaluronic acid in a tumor model of CAK-I kidney cancer cells, thus favoring the enhancement of M2 phenotype and pro-tumor properties in macrophages, laying the foundation for TAM to enhance cell migration, invasion, and angiogenesis in the TME.²¹ Therefore, CAFs-remodeled ECM can promote immunosuppressive TME formation by recruiting immunosuppressive cells. However, current studies on the recruitment of immunosuppressive cells by CAF-remodeled ECM are limited. Future research may determine whether CAFs-remodeled ECM can recruit immunosuppressive cells through signaling pathways and cytokines.

Figure 1.

CAFs-remodeled ECM promotes the formation of an immunosuppressive microenvironment in 2 ways. (1) CAFs-remodeled ECM suppresses the function of immune cells. (2) CAFs-remodeled ECM recruits immunosuppressive cells. The figure was created by Figdraw (www.figdraw.com).

Metabolic Crosstalk Between CAFs and Cancer Cells

Cancer-associated fibroblasts in TME promote an immunosuppressive microenvironment conducive to cancer cell growth and generate metabolic crosstalk with cancer cells. Cancer cells reprogram CAF metabolism by absorbing secreted metabolites such as lactate and pyruvate.²² Metabolic reprogramming of CAFs promotes malignant tumor progression by secreting ECM proteins and providing energy support.²² Therefore, understanding the specific mechanisms of metabolic crosstalk between CAFs and cancer cells may be a good way to solve the dilemma currently encountered in cancer therapy.

Cancer cells mediate the metabolic reprogramming of CAFs

Cancer cells cannot grow without sufficient protein, lipid, nucleic acid, and ATP, which must be obtained through metabolic reprogramming.²³ Cancer cells metabolic reprogramming is a key way to maintain a hypo-differentiated state and cell proliferation, but it cannot completely satisfy growth needs, requiring the manipulation of CAFs to form a compensatory environment that provides metabolic intermediates for nutrient synthesis.²⁴ Cancer cells can mediate CAF metabolic reprogramming through 3 metabolic types: glucose metabolism, amino acid metabolism, and lipid metabolism, thereby promoting their growth, metastasis, and immune escape.²⁵

Metabolic reprogramming of glucose in CAFs

The Warburg effect refers to glycolysis in cancer cells under aerobic conditions, resulting in increased glucose uptake and secretion of lactate and pyruvate.²⁶ Like the Warburg effect, CAFs exhibit changes in glucose metabolism and aerobic glycolysis that are mediated by cancer cells, referred to as the reverse “Warburg effect..”²⁶ The reverse “Warburg effect” suggests that CAFs can provide nutrients to mitochondrial oxidative phosphorylation (OXPHOS) in neighboring cancer cells through aerobic glycolysis. Currently, 2 potential mechanisms are associated with the metabolic reprogramming of glucose in CAFs, resulting in a CAFs glycolytic phenotype (Figure 2). First, CAFs enhance glycolysis by contacting the cancer cells. Cancer cells activate the p27 protein and G1/S checkpoint expression, and inhibit cyclin-dependent kinase 2 (CDK2) by upregulating 6-phosphofructokinase liver type (PFKL) and hexokinase 2 (HK2) in CAFs, thus linking the cell cycle to glycolysis and ultimately reprogramming glucose.²⁷ The oncogene c-Myc upregulates glucose transporter protein 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) expression by transactivating the LDH-A promoter, thereby enhancing glucose uptake and metabolic flux in CAFs.²⁸ In addition, small extracellular vesicles (sEVs) secreted by cancer cells increase GLUT-1 levels in CAFs by downregulating miR-186 levels, thereby enhancing glycolysis.²⁹ Small extracellular vesicles are secreted by almost all cells, surrounded by a lipid bilayer, and carry various biomolecules, including DNA, RNA, lipids, glycans, proteins, and metabolites, providing a delivery vehicle for metabolic crosstalk between cancer cells and CAFs.³⁰ Second, CAFs produce lactate and pyruvate when in contact with cancer cells. In osteosarcoma cells, cancer cells use monocarboxylate transporter 1 (MCT-1) to deliver lactate to CAFs for metabolic energy.³¹ Cancer cells in the bladder and breast produce excess lactate and upregulate MCT-4 expression in CAFs by activating MMP-9, thus enhancing the CAF ability to take up glucose.³² Moreover, pancreatic cancer cells increase lactate dehydrogenase, pyruvate kinase, and mRNA expression in CAFs by upregulating succinate dehydrogenase (SDH), fumarate hydratase (FH), and MCT1 levels, increasing lactate production and glucose uptake in CAFs and ultimately promoting pancreatic cancer invasion and migration.³³ Notably, Cavilin-1 (Cav-1) is a membrane-bound scaffold protein that partitions and negatively regulates signal transduction.³⁴ Proteomic analysis revealed that loss of Cav-1 expression in CAFs upregulates LDH-B and PKM2 levels, activating the TME and providing lactate and pyruvate for cancer cell growth, ultimately promoting the development and metastasis of prostate and breast cancers.³⁵ This may be related to the fact that Cav-1 deficiency promotes paracrine signaling mechanisms, including fibrosis, ECM remodeling, and CAF metabolic reprogramming. However, the mechanism by which cancer cells and Cav-1-deficient CAFs produce metabolic crosstalk remains to be investigated. Taken together, cancer cells can mediate metabolic reprogramming of glucose in CAFs to provide energy for their progression and metastasis.

Figure 2.

Metabolic reprogramming of glucose in CAFs. Metabolic reprogramming of glucose in CAFs. Created with BioRender.com.

Metabolic reprogramming of amino acids in CAFs

Cancer-associated fibroblasts can enhance the output of amino acids as an energy source, in addition to glucose, to meet the demands of the rapid proliferation of cancer cells (Figure 3). Glutamine (Gln), the most widely studied amino acid, is a major carbon and nitrogen source that is essential for mitochondrial metabolism in cancer cells.³⁶ Glutamine fuels tumor cell mitochondria by supplementing the tricarboxylic acid (TCA) cycle with oxaloacetic acid and accumulating intermediates, thereby promoting rapid cancer cell proliferation, which makes Gln a more critical source of ATP than glucose.³⁷ Moreover, Gln is essential for maintaining cancer cell integrity and mitochondrial membrane potential.³⁸ Cancer-associated fibroblasts, mediated by cancer cells, are required for cancer cell invasion and metastasis through upregulation of Gln metabolism. Sazeides et al³⁹ found significantly higher levels of ¹³C-labeled m+ 5α-KG and m+ 5 glutamate in ¹³C5-glutamine labeling experiments while studying the relationship between sEVs and mitochondria in prostate cancer patients, indicating that prostate cancer cells can mediate CAFs to upregulate Gln metabolism and alter their metabolic patterns, thus satisfying the dependence of sEVs and mitochondria on Gln. In ovarian cancer, cancer cells mediate CAFs to produce large amounts of Gln using glutamine synthetase (GS), which sets the stage for further conversion of Gln to glutamate and into the TCA cycle, ultimately promoting tumor progression. However, more studies are needed to demonstrate whether glutamine can promote CAF metabolic reprogramming in other cancers, and the mechanisms involved remain unclear.⁴⁰ In addition to Gln, CAFs produce other amino acids as nitrogen sources that provide nutrition to cancer cells. In p62k CAFs, despite the lack of Gln, its expression through upregulation of pyruvate carboxylase (PC) and asparagine synthetase (ASNS) can regulate pyruvate and aspartate synthesis, thereby enhancing the TCA cycle and sustaining cancer cell survival.⁴¹ In addition, human skin squamous carcinoma (HSSC) cells mediate glutamate and aspartic acid utilization by CAFs through the solute carrier family 1 membrane 3 (SLC1A3) channel, thus promoting cancer cell proliferation and biosynthesis.⁴² In summary, CAFs provide important energy support for malignant cancer progression by altering their amino acid metabolic levels.

Figure 3.

Three metabolic types associated with the metabolic reprogramming of CAFs. Metabolic reprogramming of amino acids in CAFs. Metabolic reprogramming of lipid in CAFs. Created with BioRender.com.

Metabolic reprogramming of lipid in CAFs

Lipids are natural compounds that are insoluble in water but soluble in nonpolar solvents.⁴³ Fatty acids (FAs) are important lipids, because they serve as structural components of cell membranes and second messengers involved in intracellular signal transmission.⁴⁴ Additionally, it is a source of energy when scarce or restricted.⁴⁴ Several recent studies have demonstrated that dysregulated lipid metabolism in CAFs, mediated by cancer cells, can promote tumor growth and metastasis.45^-47 In ovarian cancer, lysophosphatidic acid (LPA) derived from cancer cells mediates intracellular liposome remodeling in CAFs through hypoxia-inducible factor (HIF-1α) upregulation by the LPA receptor (LPAR), thereby promoting tumor proliferation and metabolism.⁴⁵ In colorectal cancer (CRC), CAFs increase FA production by activating fatty acid synthase (FASN), leading to lipid metabolism reprogramming and promoting uptake by CRC cells, which enhances the metastatic ability of CRC cells.⁴⁶ Moreover, in breast cancer, CAFs promote the uptake of exogenous fatty acids by cancer cells by upregulating fatty acid transporter protein 1 (FATP1) upregulation in human MDA-MB-231 TNBC cells.⁴⁷ Thus, cancer cells can mediate lipid metabolic reprogramming in CAFs to provide energy for progression and metastasis. However, recent studies have demonstrated that the mechanisms promoting lipid metabolism reprogramming in CAFs vary in different cancers. Future research should investigate whether mechanisms applicable to most cancers can mediate lipid metabolism reprogramming.

CAF metabolic reprogramming affects tumor progression

Cancer-associated fibroblast metabolic reprogramming promotes tumor progression by reshaping the metabolic levels of cancer cells in 3 important ways: exporting nutrients, regulating metabolic enzymes, and suppressing immune responses (Table 1).

Table 1.

Metabolic reprogramming of CAFs promotes tumor progression in multiple ways.

Type	Tumor	Possible mechanism	Reference
Exporting nutrients	Prostate cancer	CAFs-derived sEVs increase glutamate-dependent glycolysis and reductive carboxylation in cancer cells by inhibiting oxidative phosphorylation in mitochondria, thereby providing amino acids to nutrient-deficient cancer cells	Bertero et al⁴²
	Lymphoma cancer	CAFs-derived sEVs increase glycolysis and ATP	Koundouros and Poulogiannis⁴⁴
	Breast cancer	CAFs-derived exosomes inhibit mitochondrial oxidative phosphorylation by increasing PKM expression and decreasing miR-330-5p expression, thereby increasing glycolysis and reductive carboxylation	Radhakrishnan et al⁴⁵
Regulating metabolic enzymes	Ovarian cancer	CAFs use TGF-β to promote glycogenolysis and induce phosphorylation of PGM1 by secreting CXCL10, IL-6 and IL-8, thereby activating PPP and promoting glycolysis in ovarian cancer cells	Gong et al⁴⁶
	Ovarian cancer	CAFs enhance glycolysis and metabolism in ovarian cancer cells by upregulating the glycolytic enzyme LINC00092 level through high CXCL14 expression in vitro and in vivo	Lopes-Coelho et al⁴⁷
	HNSCC	CAFs affected by lactate upregulate glycolytic enzymes (phosphofructokinase and hexokinase II) expression by secreting hepatocyte growth factor (HGF), thereby promoting glycolysis in cancer cells	Ruivo et al⁴⁸
	Pancreatic cancer	CAFs increase Ccl6 and Ccl12 secretion and activate protein kinase A in malignant cells by depleting FAK, thus enhancing paracrine signaling of tumor proliferation and cancer cell glycolysis	Zhao et al⁴⁹
Suppressing immune responses	Ovarian cancer	CAFs inhibit CD8 + T-cell toxic activity and induce T-cell anergy by secreting IDO	Achreja et al⁵⁰
	Lung cancer	CAFs complex WNK1 and CREB by secreting kynurenine and overexpressing TDO2, thus inhibiting differentiated dendritic cells	Kunou et al⁵¹
		CAFs that undergo cancer cell-mediated reprogramming suppress neutrophils via the IL6/ signal transducer and STAT3 axis and the CCL2-CCR-2 axis, thereby enhancing MSC transformation	Curtis et al⁵²
	Hepatocellular carcinoma	CAFs lead to neutrophil apoptosis through activation of c-Jun kinase and STAT3-programmed cell death ligand 1	Zhao et al⁵³
		CAFs in hypoxic environments enhance PD-L1 expression in MDSCs by binding to the PD-L1 proximal promoter and HIF-1α, leading cancer cells to evade immune surveillance	Demircioglu et al⁵⁴

Abbreviations: CAF, cancer-associated fibroblast; CREB, cAMP response element-binding protein; FAK, focal adhesion kinase; HGF, hepatocyte growth factor; HNSCC, head and neck squamous cell carcinomas; IDO, indoleamine 2,3-dioxygenase; MDSC, myeloid-derived suppressor cell; PGM, phosphoglucomutase; PKM, pyruvate kinase M; sEVs, small extracellular vesicles; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor; WNK1, WNK Lysine Deficient Protein Kinase 1.

CAFs promote tumor progression by exporting nutrients

During metabolic reprogramming, CAFs produce numerous nutrients that cancer cells absorb to promote tumor growth. Small extracellular vesicles, approximately 100 nm in diameter, contain biologically active components such as proteins, lipids, miRNAs, and mRNAs, which change the biological properties of the recipient cells and mediate the exchange of substances between cells.⁴⁸ Recent studies have discovered that sEVs act as delivery vehicles in the metabolic crosstalk between CAFs and cancer cells, where they are internalized by cancer cells and transfer metabolites (such as proteins, mRNAs, miRNAs, and long non-coding RNA [lncRNAs]) from CAFs to tumor cells, thereby promoting tumor progression and metastasis.^49-51 In ¹³C isotope labeling experiments, prostate cancer CAF-derived sEVs increased glutamate-dependent glycolysis and reductive carboxylation in cancer cells by inhibiting OXPHOS in mitochondria, thereby providing amino acids to nutrient-deficient cancer cells to promote tumor progression.⁴⁹ Similarly, ultrahigh-performance liquid chromatography (UPLC) and gas chromatograph-mass spectrometry (GC-MS) experiments demonstrated that prostate cancer CAF-derived sEVs are rich in metabolites, such as TCA cycle intermediates, amino acids, and lipids, which are used as nutrients for tumor progression.⁵⁰ In addition, lymphoma CAF-derived sEVs can increase glycolysis and ATP levels, thereby promoting lymphoma cell growth.⁵¹ However, the metabolites carried by lymphoma CAF-derived sEVs and their relationship with glycolysis have not been investigated; this may be demonstrated in the future. In addition to direct nutrient export, CAF-derived sEVs can promote glutamate-dependent reductive carboxylation and glycolysis in cancer cells by transferring substrates and noncoding RNAs (ncRNAs). Noncoding RNAs, including the previously mentioned circular RNA (circRNA), lncRNA, miRNA, and PIWI-interacting RNA (piRNA), can act as suppressors or oncogenes to influence malignancy onset, progression, and metastasis. Breast cancer CAF-derived sEVs can inhibit mitochondrial OXPHOS by increasing PKM expression and decreasing miR-330-5p expression, thereby increasing glycolysis and reductive carboxylation, ultimately enhancing breast tumor cell proliferation.⁵⁵ This indicates that ncRNAs may be targets for regulating metabolic crosstalk between cancer cells and CAFs, and in-depth studies may provide new directions for cancer therapy.

CAFs promote tumor progression by regulating metabolic enzymes

Cancer cells mediate CAF metabolic reprogramming and induce CAFs to regulate key metabolic pathway enzymes by secreting various cytokines, thereby promoting tumor proliferation and metastasis. Cancer cell-mediated CAFs use TGF-β to promote glycogenolysis and induce the phosphorylation of phosphoglucomutase 1 (PGM1) by secreting CXCL10, interleukin (IL)-6, and IL-8, thereby activating the pentose phosphate pathway (PPP) and promoting glycolysis in ovarian cancer cells, enhancing the cancer cell ability to invade and metastasize.⁵² Similarly, CAFs upregulate the glycolytic enzyme LINC00092 through high CXCL14 expression in vitro and in vivo, thereby enhancing glycolysis and metabolism in ovarian cancer cells, ultimately promoting tumor metastasis.⁵³ In head and neck squamous cell carcinomas (HNSCC), CAFs affected by lactate upregulates glycolytic enzymes (phosphofructokinase and hexokinase II) expression by secreting hepatocyte growth factor (HGF), thereby promoting glycolysis in cancer cells and tumor progression.⁵⁶ Moreover, CAFs increase Ccl6 and Ccl12 secretion and activate protein kinase A (PKA) in malignant cells by depleting FAK, thus enhancing paracrine signaling of tumor proliferation and cancer cell glycolysis.⁵⁴ A recent study found that CAFs regulate metabolism-related signaling pathways in cancer cells. Insulin-like growth factor 1 (IGF-1) secreted by CAFs can activate the mammalian target of rapamycin (mTOR) pathway by binding to the IGF-1 receptor on CRC cells, thus triggering lactate release and glucose uptake, which promotes Gln uptake and cellular channel protein SLC7A11 (solute carrier family 7, membrane 11) expression in CRC cells. This indicates that altering signaling pathways may promote tumor progression by affecting cancer cell metabolism, such as altering metabolic enzymes; however, additional relevant mechanisms remain to be discovered.

CAFs promote tumor progression by suppressing immune responses

Reprogrammed CAFs promote tumor progression by suppressing the immune response in 3 major ways. First, metabolic reprogramming of CAFs produces metabolites that suppress the immune response. Cancer-associated fibroblasts inhibit CD8⁺ T-cell toxicity and induce T-cell anergy by secreting indoleamine 2,3-dioxygenase (IDO).⁵⁷ In lung cancer, CAFs complex WNK Lysine Deficient Protein Kinase 1 (WNK1) and cAMP response element-binding protein (CREB) by secreting kynurenine and overexpressing tryptophan 2,3-dioxygenase (TDO2), thus inhibiting differentiated dendritic cells, ultimately leading to immunosuppression.⁵⁸ In addition, arginase II (ARG2) secreted by CAFs can suppress the immune response by blocking antitumor T-cells.⁵⁹ Second, reprogrammed CAFs can suppress immune responses by interacting with neutrophils. Cancer-associated fibroblasts that undergo cancer cell-mediated reprogramming suppress neutrophils via the IL6/signal transducer and activator of the transcription 3 (STAT3) axis and CCL2-CCR-2 axis, thereby enhancing mesenchymal stem cell (MSC) transformation and tumor proliferation.⁶⁰ In hepatocellular carcinoma, CAFs can lead to apoptosis of neutrophils through the activation of c-Jun kinase and STAT3-programmed cell death ligand 1, promoting tumor growth.⁶¹ Finally, metabolically reprogrammed CAFs induce hypoxic environment formation by participating in aberrant angiogenesis, thereby promoting immunosuppression of TME. Cancer-associated fibroblasts impede T-cell infiltration by secreting pro-angiogenic factors, suppressing T-cell function, and causing immunosuppression.⁶² In addition, CAFs in hypoxic environments enhance programmed death ligand 1 (PD-L1) expression in MDSCs by binding to the PD-L1 proximal promoter and HIF-1α, causing cancer cells to evade immune surveillance.⁶³

Metabolic Reprogramming of CAFs Is Involved in Cancer Therapy

Chemotherapy strategies targeting the metabolic reprogramming of CAFs

Despite the significant clearance of chemosensitive tumors by chemotherapy, many tumor cells remain viable owing to tumor heterogeneity (Figure 4). Tumor heterogeneity refers to the specific phenotypic characteristics of different cell populations in tumors, including intratumor, intermetastatic, intrametastatic, and interpatient tumor heterogeneity. This is the primary reason for the survival of tumor cells with intrinsic or acquired drug resistance.⁶⁴ Surviving tumor cells induce CAFs to secrete chemokines by mediating the metabolic reprogramming of CAFs, thereby enhancing invasiveness and resistance to chemotherapeutic agents, ultimately leading to tumor drug resistance.⁶⁵ Currently, several potential chemotherapeutic strategies targeting the metabolic reprogramming of CAFs may improve the dilemma encountered in cancer chemotherapy. Targeting metabolically reprogrammed CAFs using antibodies against cell surface markers (GPR77 and CD10) inhibits NF-κB activation and blocks GPR77 complement signaling caused by p65 acetylation and phosphorylation, thereby improving chemosensitivity in lung and breast cancers.⁶⁶ Docetaxel, in combination with smoothened inhibitors, can inhibit the activation of Hedgehog signaling by CAFs, thereby impeding CAF metabolic reprogramming and tumor cell resistance phenotype expression.⁶⁷ Similarly, gemcitabine inhibits fibrosis and stromal inflammation caused by CAF metabolic reprogramming by combining with vitamin D receptor (VDR) ligands, improving the pancreatic tumor ability to uptake gemcitabine and enhancing survival in pancreatic cancer patients.⁶⁸ Moreover, chemotherapy combined with a DNA vaccine targeting fibroblast activation proteins (FAPs) enhances CD8T cells ability to kill CAFs, thereby improving the body’s ability to absorb chemotherapeutic drugs.⁶⁹ Interestingly, a recent study discovered that rhythmic therapy, in which low doses are administered on a frequent or continuous schedule, can inhibit CAFs from secreting paracrine signals for metabolic reprogramming, thereby inhibiting tumor progression and enhancing chemotherapeutic efficacy.⁷⁰ However, these strategies are still experimental and have not yet been tested for their clinical relevance. Further research is needed to determine whether these strategies apply to clinical treatment.

Figure 4.

Metabolic reprogramming of CAFs is involved in cancer therapy. (1) Chemotherapy strategies targeting the metabolic reprogramming of CAFs; (2) immunotherapeutic strategies targeting the CAF metabolic reprogramming: (1) Direct action on CAFs targets to deplete CAFs; (2) Limiting CAFs-induced ECM remodeling to inhibit tumor progression. Created with BioRender.com.

Immunotherapeutic strategies targeting the CAF metabolic reprogramming

Immunotherapy is emerging as one of the most promising methods for targeting the metabolic reprogramming of CAFs to inhibit tumor proliferation by investigating the link between CAF metabolic reprogramming and the immunosuppressive microenvironment.⁷¹ There are 2 potential immunotherapeutic strategies to inhibit tumor progression by targeting CAF metabolic reprogramming: direct action on CAFs targets to deplete CAFs and restriction of CAF-induced ECM remodeling.

Direct action on CAFs targets to deplete CAFs

Immunotherapeutic strategies that act directly on CAFs deplete CAF metabolic reprogramming using inhibitors of CAF surface markers. Fibroblast activation protein, the most popular surface marker for CAFs, enhances the toxic effects of CD8+ T-cells and promotes tumor necrosis factor (TNF)-α and interferon (IFN)-γ-mediated immune responses through targeted therapies, including tumor vaccines and T-cell therapy, thereby eliminating FAP+ cells and CAFs.⁷² First, FAP-based DNA vaccines disrupt immune tolerance and eliminate CAFs by promoting CD4⁺ and CD8⁺ T-cell-mediated immune responses, thereby inhibiting tumor progression,⁷³.⁷⁴ Second, FAP-based DC vaccines impede Treg cells migration to tumors by reducing TGF-β levels and enhancing T-cell responses, thereby inhibiting CAFs with high FAP expression and ultimately suppressing tumor growth and metastasis.^75,76 Furthermore, FAP-based T-cell therapy depletes FAP-positive cells using chimeric antigen receptor (CAR) T-cells, thereby impeding tumor stroma formation and facilitating the uptake of antitumor chemotherapeutic agents (such as gemcitabine).⁷⁷ However, considerable challenges remain concerning FAP-based therapies. Certain tumor vaccines, such as peptide immune vaccines, whole-cell vaccines, and adenoviral vector vaccines, are not the same for CAFs, even though they can destroy FAP+ stromal cells. The mechanisms by which other FAP-targeted therapies, including FAP-targeted liposomes, immunotoxins, antibodies, and cisplatin, affect metabolic reprogramming of CAFs remain to be investigated. Notably, α-SMA, another surface marker of CAFs, is closely associated with CAF metabolic reprogramming.⁷⁸ In pancreatic and breast cancers, Özdemir et al⁷⁸ discovered that attenuated infiltration of CD3+ Foxp3+ Treg cells enhanced myofibroblast depletion and inhibited fibrosis, thereby depleting α-SMA + CAFs, which inhibited tumor progression and angiogenesis. However, the accuracy of FAP- and α-SMA-based immunotherapy is unsatisfactory, and highly selective surface markers of CAFs need to be discovered and investigated in depth. Table 2 displays the clinical trials of CAF metabolic reprogramming by FAP-targeted therapy.

Table 2.

Clinical trials related to metabolic reprogramming of CAFs by FAP-targeted therapy.

NCT Number	Title	Status	Conditions	Interventions	Phases
NCT05442151	Evaluation Using FAPI-PET Targeting Cancer-associated Fibroblasts	Recruiting	Neoplasms	Drug: PET/CT ([F-18] FAPI-74)	Not Applicable
NCT05262855	Study of [68Ga] FAPI-46 PET in Patients With Pancreatic Ductal Carcinoma	Recruiting	PDAC—pancreatic ductal adenocarcinomaFAP	Drug: [68Ga] FAPI-46	Phase 2
NCT05030597	Exploring the Application Value of PET Molecular Imaging Targeting FAP in Oral Squamous Cell Carcinoma	Recruiting	PET/CTFAPIOral cancer	Drug: 68Ga-DOTA-FAPIDevice: PET/CT	Not Applicable
NCT04939610	A Study of 177Lu-FAP-2286 in Advanced Solid Tumors (LuMIERE)	Recruiting	Solid tumor	Drug: 68Ga-FAP-2286Drug: 177Lu-FAP-2286	Phase 1Phase 2
NCT04621435	Imaging of Solid Tumors Using FAP-2286	Recruiting	Solid tumors, adult metastatic cancer	Drug: Gallium-68 labeled (68Ga-) FAP-2286Procedure: Positron Emission Tomography (PET) imagingDrug: Copper-64 labeled (64Cu-) FAP-2286	Phase 1
NCT04554719	Clinical Application of Fibroblast Activation Protein PET/MRI for Diagnosis and Staging in Malignant Tumors	Recruiting	Malignant neoplasm	Drug: 68Ga-DOTA-FAPIDevice: PET/MRDevice: PET/CT	Not Applicable
NCT04459273	Prospective Exploratory Study of FAPi PET/CT With Histopathology Validation in Patients With Various Cancers	Recruiting	Bladder carcinomaCervical carcinomaCholangiocarcinoma(and 12 more. . .)	Drug: Gallium Ga 68 FAPi-46Procedure: Positron Emission Tomography	Phase 1

Limiting CAFs-induced ECM remodeling to inhibit tumor progression

Considering that CAFs can promote the formation of an immunosuppressive microenvironment by remodeling the ECM, thus favoring tumor invasion and metastasis, inhibiting tumor progression by limiting CAF-induced ECM remodeling is a feasible strategy for immunotherapy. Hyaluronan (HA) and Tenascin C (TNC), the predominant CAF-derived ECM proteins, have been demonstrated to be important targets for inhibiting ECM remodeling by attenuating the pro-connective tissue proliferative response.⁷⁹ Human recombinant PH20 hyaluronidase (PEGPH20) depletion of HA by combining nab-paclitaxel and gemcitabine can reduce vascular compression and improve vascular patency, thereby inhibiting ECM remodeling, which promotes immune cell entry into the tumor vasculature and inhibits tumor progression.⁸⁰ Losartan inhibits the HA production and stromal collagen by inhibiting the compliance signaling of endothelin-1 (ET-1), connective tissue growth factor (CTGF), and TGF-β1, thereby reducing remodeled ECM component formation and decreasing the immunosuppressive effect of ECM on immune cells.⁸¹ Furthermore, antibody F16 recruits immune cells to the TME. It downregulates TNC expression in cancer tissues by complexing IL-2, thus reducing the signaling of effector molecules to TNC-rich tumor tissues, and ultimately inhibiting tumor proliferation and invasion.⁸²

Future Prospects of Targeting CAF Metabolic Reprogramming to Treat Cancer

Numerous findings have linked CAF metabolic reprogramming to cancer development, progression, and metastasis. As a new field, CAF metabolic reprogramming has great potential for tumor treatment. However, current studies on CAF metabolic reprogramming are limited to tumor model studies, leading to limited data regarding its use in clinical treatment. In the future, metabolic reprogramming targeting CAFs appears to have great potential to play a role in the clinical treatment of cancer. They may focus on the following promising aspects.

Conduct preclinical studies to determine the mechanism underlying the combined effects of multiple metabolic inhibitors and immunotherapy in CAFs. By further understanding this combined mechanism helps to improve the adjuvance of CAFs for immunotherapy, both from the perspective of reducing tumor promotion and affecting immune cells.

In-depth exploration of the impact of metabolic reprogramming of glucose, amino acids and lipids in regulating CAFs in cancer. A detailed understanding of the mechanisms can help in the development of drugs targeting relevant CAFs and their utilization.

The relationship between immune cells and CAF metabolic reprogramming remains to be understood. Immune cells are key to influencing TME, and exploring the relationship between immune cells and CAFs can further clarify the relevant mechanisms between them and tumorigenesis and development.

The role of CAF metabolic reprogramming in radiotherapy has not yet been discovered, and whether there is an association between them is also a question worth exploring. Given the relationship of CAF to chemotherapy and immunotherapy, and its associated role in TME, we hypothesized that CAF would also be able to influence chemotherapy for tumors.

While we describe the mechanisms by which metabolic reprogramming leads to tumor progression and metastasis, and its potential in chemotherapy and immunotherapy. However, this article still has certain shortcomings. In particular, it lacks the study of related clinical trials, because the current off related studies still remain at the preclinical level and need to be further explored and researched.

Conclusion

Given that CAFs have complex crosstalk with numerous cellular structures within the TME, metabolic reprogramming of CAFs plays an important role in cancer cell growth, metastasis, and immune reprogramming. Therefore, therapies targeting reprogramming of CAFs are important in oncology, especially in combination with chemotherapy and immunotherapy. However, despite the success of these inhibitors in tumor models, breakthroughs in clinical translation still require more in-depth research in related directions.

Footnotes

Acknowledgements

The Figure was created by Figdraw (www.figdraw.com) and BioRender.com. The authors thank Home for Researchers editorial team () for language editing service.

Author Contributions

LZ and WZ drafted the manuscript in detail. WZ and LZ researched the literatures and drawed figures. XH and LZ counted and plotted the diagram and table. DT and DW critically revised the article for important intellectual content. All authors read and approved the final manuscript.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding:

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Graduate Research-Innovation Project in Jiangsu province (grant no. SJCX21_1644), the Academic Science and Technology Innovation Fund for College Students (grant no. 202011117056Y), the Social Development-Health Care Project of Yangzhou, Jiangsu Province (grant no. YZ2021075), and High-level talent “six one projects” top talent scientific research project of Jiangsu Province (grant no. LGY2019034), the Graduate Research-Innovation Project in Jiangsu province (grant no. SJCX22_1816), and Social development project of key R & D plan of Jiangsu Provincial Department of science and technology (grant no. BE2022773). The funding bodies had no role in the design of the study; in the collection, analysis, and interpretation of the data; and in the writing of the manuscript.

Availability of Data and Material

Not applicable

Ethics Approval and Consent to Participate

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Consent for Publication

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ORCID iDs

Lujia Zhou

References

Farhood

Najafi

Mortezaee

Cancer-associated fibroblasts: secretions, interactions, and therapy. J Cell Biochem. 2019;120:2791-2800. doi:10.1002/jcb.27703

Comito

Ippolito

Chiarugi

Cirri

Nutritional exchanges within tumor microenvironment: impact for cancer aggressiveness. Front Oncol. 2020;10:396. doi:10.3389/fonc.2020.00396

Faubert

Solmonson

DeBerardinis

RJ.

Metabolic reprogramming and cancer progression. Science. 2020;368:eaaw5473. doi:10.1126/science.aaw5473

Ribeiro Franco

Rodrigues

de Menezes

Pacheco Miguel

Tumor microenvironment components: allies of cancer progression. Pathol Res Pract. 2020;216:152729. doi:10.1016/j.prp.2019.152729

Yang

Zou

Zhu

Role of exosomes in crosstalk between cancer-associated fibroblasts and cancer cells. Front Oncol. 2019;9:356. doi:10.3389/fonc.2019.00356

Wang

Zeng

, et al. TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation. Cell Death Discov. 2022;8:3. doi:10.1038/s41420-021

Eble

Niland

The extracellular matrix in tumor progression and metastasis. Clin Exp Metastasis. 2019;36:171-198. doi:10.1007/s10585-019-09966-1

Erdogan

Webb

DJ.

Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 2017;45:229-236. doi:10.1042/bst20160387

Chakravarthy

Khan

Bensler

Bose

De Carvalho

DD.

TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun. 2018;9:4692. doi:10.1038/s41467-018

10.

Calvo

Ege

Grande-Garcia

, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637-646. doi:10.1038/ncb2756

11.

Liu

Ren

You

Zhao

The significant role of amino acid metabolic reprogramming in cancer. Cell Commun Signal. 2024;22:380. doi:10.1186/s12964-024

12.

Mao

Wang

, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20:131. doi:10.1186/s12943-021

13.

Yuan

Wang

YX.

Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion. Cancer Immunol Immunother. 2024;73:115. doi:10.1007/s00262-024

14.

Blair

Kim

Muth

, et al. Dissecting the stromal signaling and regulation of myeloid cells and memory effector T cells in pancreatic cancer. Clin Cancer Res. 2019;25:5351-5363. doi:10.1158/1078-0432.CCR-18-4192

15.

Herrera

Ronet

Ochoa

Olza

, et al. Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy. Cancer Discov. 2022;12:108-133. doi:10.1158/2159-8290.Cd-21-0003

16.

Jiang

Hegde

Knolhoff

, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22:851-860. doi:10.1038/nm.4123

17.

Kuo

KK.

Cancer-derived extracellular succinate: a driver of cancer metastasis. J Biomed Sci. 2022;29:93. doi:10.1186/s12929-022

18.

Krishnamoorthy

Gerhardt

Maleki Vareki

Immunosuppressive effects of myeloid-derived suppressor cells in cancer and immunotherapy. Cells. 2021;10:1170. doi:10.3390/cells10051170

19.

Serrels

Lund

Serrels

, et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015;163:160-173. doi:10.1016/j.cell.2015.09.001

20.

Varol

Tumorigenic interplay between macrophages and collagenous matrix in the tumor microenvironment. Methods Mol Biol. 2019;1944:203-220. doi:10.1007/978-1-4939-9095-5_15

21.

Tajaldini

Saeedi

Amiriani

, et al. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs); where do they stand in tumorigenesis and how they can change the face of cancer therapy? Eur J Pharmacol. 2022;928:175087. doi:10.1016/j.ejphar.2022.175087

22.

Sahai

Astsaturov

Cukierman

, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20:174-186. doi:10.1038/s41568-019-0238-1

23.

Vander Heiden

DeBerardinis

RJ.

Understanding the intersections between metabolism and cancer biology. Cell. 2017;168:657-669. doi:10.1016/j.cell.2016.12.039

24.

Chiarugi

Cirri

Metabolic exchanges within tumor microenvironment. Cancer Lett. 2016;380:272-280. doi:10.1016/j.canlet.2015.10.027

25.

Arcucci

Ruocco

Granato

Sacco

Montagnani

Cancer: an oxidative crosstalk between solid tumor cells and cancer associated fibroblasts. Biomed Res Int. 2016;2016:4502846. doi:10.1155/2016/4502846

26.

Liberti

Locasale

JW.

The Warburg effect: how does it benefit cancer cells?

Trends Biochem Sci. 2016;41:211-218. doi:10.1016/j.tibs.2015.12.001

27.

Sun

Zhang

Xiong

Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts. Cell Signal. 2014;26:2210-2216. doi:10.1016/j.cellsig.2014.04.015

28.

Sun

Xiong

miR-186 regulates glycolysis through Glut1 during the formation of cancer-associated fibroblasts. Asian Pac J Cancer Prev. 2014;15:4245-4250. doi:10.7314/apjcp.2014.15.10.4245

29.

Affinito

Quintavalle

Chianese

, et al. MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p. Cell Death Discov. 2024;10:140. doi:10.1038/s41420-024

30.

Mathieu

Martin-Jaular

Lavieu

Théry

Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9-17. doi:10.1038/s41556-018-0250-9

31.

Bonuccelli

Avnet

Grisendi

, et al. Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells. Oncotarget. 2014;5:7575-7588. doi:10.18632/oncotarget.2243

32.

Peppicelli

Bianchini

Calorini

Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014;33:823-832. doi:10.1007/s10555-014-9506-4

33.

Shan

Chen

, et al. Cancer-associated fibroblasts enhance pancreatic cancer cell invasion by remodeling the metabolic conversion mechanism. Oncol Rep. 2017;37:1971-1979. doi:10.3892/or.2017.5479

34.

Sotgia

Martinez-Outschoorn

Howell

Pestell

Pavlides

Lisanti

MP.

Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol. 2012;7:423-467. doi:10.1146/annurev-pathol-011811-120856

35.

Sung

Kang

, et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene. 2020;39:664-676. doi:10.1038/s41388-019-1014-0

36.

Zhuo

Wang

Metabolic reprogramming of carcinoma-associated fibroblasts and its impact on metabolic heterogeneity of tumors. Semin Cell Dev Biol. 2017;64:125-131. doi:10.1016/j.semcdb.2016.11.003

37.

Eisenberg

Eisenberg-Bord

Eisenberg-Lerner

Sagi-Eisenberg

Metabolic alterations in the tumor microenvironment and their role in oncogenesis. Cancer Lett. 2020;484:65-71. doi:10.1016/j.canlet.2020.04.016

38.

Leone

Zhao

Englert

, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019;366:1013-1021. doi:10.1126/science.aav2588

39.

Sazeides

Metabolic relationship between cancer-associated fibroblasts and cancer cells. Adv Exp Med Biol. 2021;1311:189-204. doi:10.1007/978-3-030-65768-0_14

40.

Yang

Achreja

Yeung

, et al. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab. 2016;24:685-700. doi:10.1016/j.cmet.2016.10.011

41.

Linares

Cordes

Duran

, et al. ATF4-induced metabolic reprograming is a synthetic vulnerability of the p62-deficient tumor stroma. Cell Metab. 2017;26:817-829.e816. doi:10.1016/j.cmet.2017.09.001

42.

Bertero

Oldham

Grasset

, et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 2019;29:124-140.e110. doi:10.1016/j.cmet.2018.09.012

43.

Munir

Lisec

Swinnen

Zaidi

Lipid metabolism in cancer cells under metabolic stress. Br J Cancer. 2019;120:1090-1098. doi:10.1038/s41416-019-0451-4

44.

Koundouros

Poulogiannis

Reprogramming of fatty acid metabolism in cancer. Br J Cancer. 2020;122:4-22. doi:10.1038/s41416-019-0650-z

45.

Radhakrishnan

Jayaraman

, et al. Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts. Cancer Lett. 2019;442:464-474. doi:10.1016/j.canlet.2018.11.023

46.

Gong

Lin

Zhang

, et al. Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis. 2020;11:267. doi:10.1038/s41419-020

47.

Lopes-Coelho

André

Félix

Serpa

Breast cancer metabolic cross-talk: fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol. 2018;462:93-106. doi:10.1016/j.mce.2017.01.031

48.

Ruivo

Adem

Silva

Melo

SA.

The biology of cancer exosomes: insights and new perspectives. Cancer Res. 2017;77:6480-6488. doi:10.1158/0008-5472.Can-17-0994

49.

Zhao

Yang

Baddour

, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife. 2016;5:e10250. doi:10.7554/eLife.10250

50.

Achreja

Zhao

Yang

Yun

Marini

Nagrath

Exo-MFA—a 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism. Metab Eng. 2017;43:156-172. doi:10.1016/j.ymben.2017.01.001

51.

Kunou

Shimada

Takai

, et al. Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma. Oncogene. 2021;40:3989-4003. doi:10.1038/s41388-021-01829-y

52.

Curtis

Kenny

Ashcroft

, et al. Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab. 2019;29:141-155.e149. doi:10.1016/j.cmet.2018.08.007

53.

Zhao

, et al. Long noncoding RNA LINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer. Cancer Res. 2017;77:1369-1382. doi:10.1158/0008-5472.Can-16-1615

54.

Demircioglu

Wang

Candido

, et al. Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat Commun. 2020;11:1290. doi:10.1038/s41467-020

55.

Zhao

Liu

SNHG3 functions as miRNA sponge to promote breast cancer cells growth through the metabolic reprogramming. Appl Biochem Biotechnol. 2020;191:1084-1099. doi:10.1007/s12010-020-03244-7

56.

Kumar

New

Vishwakarma

, et al. Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. Cancer Res. 2018;78:3769-3782. doi:10.1158/0008-5472.Can-17-1076

57.

Chen

Kuo

Tsai

Hou

Hung

WC.

Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression. Breast Cancer Res. 2014;16:410. doi:10.1186/s13058-014

58.

Hsu

Hung

Chiang

, et al. Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget. 2016;7:27584-27598. doi:10.18632/oncotarget.8488

59.

Huang

Brekken

RA.

Recent advances in understanding cancer-associated fibroblasts in pancreatic cancer. Am J Physiol Cell Physiol. 2020;319:C233-C243. doi:10.1152/ajpcell.00079.2020

60.

Zhu

Zhang

, et al. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis. 2014;5:e1295. doi:10.1038/cddis.2014.263

61.

Cheng

Deng

, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9:422. doi:10.1038/s41419-018

62.

Chouaib

Noman

Kosmatopoulos

Curran

MA.

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017;36:439-445. doi:10.1038/onc.2016.225

63.

Zhu

Wang

Hong

Yang

Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment. Front Endocrinol (Lausanne). 2022;13:988295. doi:10.3389/fendo.2022.988295

64.

Jamal-Hanjani

Quezada

Larkin

Swanton

Translational implications of tumor heterogeneity. Clin Cancer Res. 2015;21:1258-1266. doi:10.1158/1078-0432.Ccr-14-1429

65.

Fiori

Di Franco

Villanova

Bianca

Stassi

De Maria

Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18:70. doi:10.1186/s12943-019

66.

Chen

Yao

, et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 2018;172:841-856.e816. doi:10.1016/j.cell.2018.01.009

67.

Cazet

Hui

Elsworth

, et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat Commun. 2018;9:2897. doi:10.1038/s41467-018

68.

Miao

Liu

Lin

, et al. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Res. 2017;77:719-731. doi:10.1158/0008-5472.Can-16-0866

69.

Duperret

Trautz

Ammons

, et al. Alteration of the tumor stroma using a consensus DNA vaccine targeting fibroblast activation protein (FAP) synergizes with antitumor vaccine therapy in mice. Clin Cancer Res. 2018;24:1190-1201. doi:10.1158/1078-0432.Ccr-17-2033

70.

Chan

Hsu

Pai

, et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med. 2016;213:2967-2988. doi:10.1084/jem.20151665

71.

Darvin

Toor

Sasidharan Nair

Elkord

Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50:1-11. doi:10.1038/s12276-018-0191-1

72.

Nurmik

Ullmann

Rodriguez

Haan

Letellier

In search of definitions: cancer-associated fibroblasts and their markers. Int J Cancer. 2020;146:895-905. doi:10.1002/ijc.32193

73.

Puré

Blomberg

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. Oncogene. 2018;37:4343-4357. doi:10.1038/s41388-018-0275-3

74.

Xia

Geng

Zhang

, et al. Cyclophosphamide enhances anti-tumor effects of a fibroblast activation protein α-based DNA vaccine in tumor-bearing mice with murine breast carcinoma. Immunopharmacol Immunotoxicol. 2017;39:37-44. doi:10.1080/08923973.2016.1269337

75.

Qian

Tang

Yin

, et al. Fusion of dendritic cells and cancer-associated fibroblasts for activation of anti-tumor cytotoxic T lymphocytes. J Biomed Nanotechnol. 2018;14:1826-1835. doi:10.1166/jbn.2018.2616

76.

Meng

Wang

Yan

, et al. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model. Tumour Biol. 2016;37:10317-10327. doi:10.1007/s13277-016-4825-4

77.

Wang

Scholler

, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800-2810. doi:10.1158/0008-5472.Can-14-3041

78.

Özdemir

Pentcheva-Hoang

Carstens

, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2015;28:831-833. doi:10.1016/j.ccell.2015.11.002

79.

McCarthy

El-Ashry

Turley

EA.

Hyaluronan, cancer-associated fibroblasts and the tumor microenvironment in malignant progression. Front Cell Dev Biol. 2018;6:48. doi:10.3389/fcell.2018.00048

80.

Doherty

Tempero

Corrie

PG.

HALO-109-301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14:13-22. doi:10.2217/fon-2017-0338

81.

Chauhan

Martin

Liu

, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4:2516. doi:10.1038/ncomms3516

82.

Zhang

Huang

, et al. Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation. Nat Commun. 2020;11:3806. doi:10.1038/s41467-020

Metabolic Reprogramming of Cancer-Associated Fibroblast in the Tumor Microenvironment: From Basics to Clinic

Abstract

Keywords

Introduction

Crosstalk Between CAFs and ECM: Promoting Immunosuppressive TME Formation

Metabolic Crosstalk Between CAFs and Cancer Cells

Cancer cells mediate the metabolic reprogramming of CAFs

Metabolic reprogramming of glucose in CAFs

Metabolic reprogramming of amino acids in CAFs

Metabolic reprogramming of lipid in CAFs

CAF metabolic reprogramming affects tumor progression

CAFs promote tumor progression by exporting nutrients

CAFs promote tumor progression by regulating metabolic enzymes

CAFs promote tumor progression by suppressing immune responses

Metabolic Reprogramming of CAFs Is Involved in Cancer Therapy

Chemotherapy strategies targeting the metabolic reprogramming of CAFs

Immunotherapeutic strategies targeting the CAF metabolic reprogramming

Direct action on CAFs targets to deplete CAFs

Limiting CAFs-induced ECM remodeling to inhibit tumor progression

Future Prospects of Targeting CAF Metabolic Reprogramming to Treat Cancer

Conclusion

Footnotes

Acknowledgements

Author Contributions

Declaration of conflicting interests:

Funding:

Availability of Data and Material

Ethics Approval and Consent to Participate

Consent for Publication

ORCID iDs

References