Novel anti-tumor strategies: targeting the crosstalk between cancer stem cells and cancer-associated fibroblasts to resist drug resistance

Abstract

The reciprocal feedback between cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) is increasingly recognized as a driver of therapeutic resistance and tumor evolution. According to the “soil and seed” hypothesis, CAFs create a biochemical and biomechanical “soil” for CSCs to seed, grow, and thrive. In turn, CSCs manipulate and transform fibroblasts to promote CSC traits, thus completing the loop of CAF-CSC crosstalk through bidirectional molecular communication within the tumor microenvironment. This review encompasses recent advances in CAF heterogeneity, including conserved and malignancy-specific subtypes, as well as the molecular dialogue driving resistance. We also briefly discuss emerging therapeutic approaches, particularly the potential of natural compounds to target both CSCs and CAFs. By bridging mechanistic insights with translational innovations, this review provides a roadmap for breaking the CSC-CAF alliance, offering hope for overcoming therapeutic resistance and improving cancer outcomes.

Keywords

Cancer stem cell / cancer-associated fibroblast / tumor microenvironment / stromal reprogramming / therapeutic resistance

References

[1] Bonnet D.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med1997;3:730-7

[2] Al-Hajj M,Benito-Hernandez A,Clarke MF.Prospective identification of tumorigenic breast cancer cells.Proc Natl Acad Sci U S A2003;100:3983-8 PMCID:PMC153034

[3] Xie XP,Sun D.Quiescent human glioblastoma cancer stem cells drive tumor initiation, expansion, and recurrence following chemotherapy.Dev Cell2022;57:32-46.e8 PMCID:PMC8820651

[4] Zhang S,Godoy C,Liu QJ.GPR56 drives colorectal tumor growth and promotes drug resistance through upregulation of MDR1 expression via a RhoA-mediated mechanism.Mol Cancer Res2019;17:2196-207 PMCID:PMC6913243

[5] Elhanani O,Keren L.Spatial profiling technologies illuminate the tumor microenvironment.Cancer Cell2023;41:404-20

[6] Talbott HE,Griffin M,Longaker MT.Wound healing, fibroblast heterogeneity, and fibrosis.Cell Stem Cell2022;29:1161-80 PMCID:PMC9357250

[7] Chu X,Ning J.Cancer stem cells: advances in knowledge and implications for cancer therapy.Signal Transduct Target Ther2024;9:170 PMCID:PMC11224386

[8] Zhang S,Chen Y.CAFs-derived lactate enhances the cancer stemness through inhibiting the MST1 ubiquitination degradation in OSCC.Cell Biosci2024;14:144 PMCID:PMC11603751

[9] Huang YJ,Yadav VK et al.Preclinical investigation of ovatodiolide as a potential inhibitor of colon cancer stem cells via downregulating sphere-derived exosomal beta-catenin/STAT3/miR-1246 cargoes.Am J Cancer Res2020;10:2337-54 PMCID:PMC7471366

[10] Zhang D,Shen L.Exosomes derived from Piwil2-induced cancer stem cells transform fibroblasts into cancer-associated fibroblasts.Oncol Rep2020;43:1125-32 PMCID:PMC7057936

[11] González-Callejo P,Díaz-Riascos ZV.Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs.Int J Cancer2023;152:2153-65

[12] Muralidharan H,Steinle A,Stickeler E.Breast cancer stem cells upregulate IRF6 in stromal fibroblasts to induce stromagenesis.Cells2024;13:1466 PMCID:PMC11393902

[13] Ji Z,Gao W,Wang H.Cancer-associated fibroblast-derived interleukin-8 promotes ovarian cancer cell stemness and malignancy through the Notch3-mediated signaling.Front Cell Dev Biol2021;9:684505 PMCID:PMC8280773

[14] Luo H,Huang LB.Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.Nat Commun2022;13:6619 PMCID:PMC9636408

[15] Mitra AK,Hua Y.MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer.Cancer Discov2012;2:1100-8 PMCID:PMC3685866

[16] Gao Y,Cheng W.Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation.Cancer Cell2024;42:1764-83.e10

[17] Xu J,Dong X.Hypoxia-induced upregulation of HIF1A-AS3 promotes MSC transition to cancer-associated fibroblasts and confers drug resistance in gastric cancer.Drug Resist Updat2025;82:101275

[18] Nair N,Zahra MH.A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment.Sci Rep2017;7:6838 PMCID:PMC5533745

[19] Qiu H,Qi J.Identification and characterization of FGFR2⁺ hematopoietic stem cell-derived fibrocytes as precursors of cancer-associated fibroblasts induced by esophageal squamous cell carcinoma.J Exp Clin Cancer Res2022;41:240 PMCID:PMC9358838

[20] Tang PC,Chung JY.Hematopoietic transcription factor RUNX1 is essential for promoting macrophage-myofibroblast transition in non-small-cell lung carcinoma.Adv Sci2024;11:e2302203 PMCID:PMC10767400

[21] Peng H,Feng K,Zhang Y.Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.Signal Transduct Target Ther2024;9:169 PMCID:PMC11220018

[22] Tao J,Zhang Z.CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment.J Exp Clin Cancer Res2024;43:277 PMCID:PMC11448066

[23] Sahai E,Cukierman E.A framework for advancing our understanding of cancer-associated fibroblasts.Nat Rev Cancer2020;20:174-86 PMCID:PMC7046529

[24] Cao Z,Arora S.Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects.J Biomed Sci2025;32:7 PMCID:PMC11715488

[25] Elyada E,Laise P.Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts.Cancer Discov2019;9:1102-23 PMCID:PMC6727976

[26] Öhlund D,Biffi G.Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.J Exp Med2017;214:579-96 PMCID:PMC5339682

[27] Cords L,Bodenmiller B.Classifying cancer-associated fibroblasts-The good, the bad, and the target.Cancer Cell2024;42:1480-5

[28] Cords L,Anzeneder T.Cancer-associated fibroblast classification in single-cell and spatial proteomics data.Nat Commun2023;14:4294 PMCID:PMC10354071

[29] Özdemir BC,Carstens JL.Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.Cancer Cell2014;25:719-34 PMCID:PMC4180632

[30] Rhim AD,Thomas DH.Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.Cancer Cell2014;25:735-47 PMCID:PMC4096698

[31] Kieffer Y,Gentric G.Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer.Cancer Discov2020;10:1330-51

[32] Honda CK,Fujii T.Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-β activity and CD8⁺ T-cell infiltration in breast cancer.Theranostics2024;14:1873-85 PMCID:PMC10945331

[33] Wang Y,Xu H.Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.Cell Discov2021;7:36 PMCID:PMC8149399

[34] Chen B,Xie F.The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional atlas.Clin Transl Med2023;13:e1516 PMCID:PMC10751516

[35] Lambrechts D,Boeckx B.Phenotype molding of stromal cells in the lung tumor microenvironment.Nat Med2018;24:1277-89

[36] Zhang M,Wan L.Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma.J Hepatol2020;73:1118-30

[37] Krishnamurty AT,Thai M.LRRC15⁺ myofibroblasts dictate the stromal setpoint to suppress tumour immunity.Nature2022;611:148-54 PMCID:PMC9630141

[38] Cords L,Haberecker M.Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer.Cancer Cell2024;42:396-412.e5 PMCID:PMC10929690

[39] Salmon H,Damotte D.Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors.J Clin Invest2012;122:899-910 PMCID:PMC3287213

[40] Kraman M,Arnold JN.Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.Science2010;330:827-30

[41] Kim N,Lee K.Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma.Nat Commun2020;11:2285 PMCID:PMC7210975

[42] Sun C,Ni C.Transgelin promotes lung cancer progression via activation of cancer-associated fibroblasts with enhanced IL-6 release.Oncogenesis2023;12:18 PMCID:PMC10060230

[43] Yan Y,Hu J.Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung cancer.Nat Genet2025;57:126-39

[44] Chen C,Liu Y.Single-cell and spatial transcriptomics reveal POSTN⁺ cancer-associated fibroblasts correlated with immune suppression and tumour progression in non-small cell lung cancer.Clin Transl Med2023;13:e1515 PMCID:PMC10731139

[45] Wang H,Liu Z.POSTN⁺ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.J Immunother Cancer2024;12:e008721 PMCID:PMC11284881

[46] Wong HY,Hesterberg AB.Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease.Nat Commun2022;13:6036 PMCID:PMC9562361

[47] Li H,Sengupta D.Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors.Nat Genet2017;49:708-18

[48] Hornburg M,Lu S.Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer.Cancer Cell2021;39:928-44.e6

[49] Xu J,Chen K.Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer.Clin Cancer Res2022;28:3590-602 PMCID:PMC9662915

[50] Biffi G,Spielman B.IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma.Cancer Discov2019;9:282-301 PMCID:PMC6368881

[51] Valdés-Mora F,Gloss BS.Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype.Cell Rep2021;35:108945

[52] Mello AM,Lee Y.Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer.Oncogenesis2022;11:56 PMCID:PMC9478137

[53] Schwörer S,Ros M.Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines.Cancer Res2023;83:1596-610 PMCID:PMC10658995

[54] Picard FSR,Brichkina A.IL-17A-producing CD8⁺ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.Gut2023;72:1510-22 PMCID:PMC10359545

[55] Cui Zhou D,Chen S.Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.Nat Genet2022;54:1390-405 PMCID:PMC9470535

[56] Zhang X,Hu C.Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair.Oncogene2022;41:2372-89 PMCID:PMC9010302

[57] Houthuijzen JM,van der Burg E.CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer.Nat Commun2023;14:183 PMCID:PMC9837080

[58] Affo S,Brundu F.Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.Cancer Cell2021;39:866-82.e11 PMCID:PMC8241235

[59] Kim J,Kim KH.Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity.NPJ Precis Oncol2022;6:9 PMCID:PMC8795238

[60] Dings MPG,Waasdorp C.Serum levels of iCAF-derived osteoglycin predict favorable outcome in pancreatic cancer.Int J Cancer2023;152:511-23 PMCID:PMC10087204

[61] Zhang G,Pan W.Dissecting the spatial and single-cell transcriptomic architecture of cancer stem cell niche driving tumor progression in gastric cancer.Adv Sci2025;12:e2413019 PMCID:PMC12079437

[62] Huang H,Zhang Y.Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer.Cancer Cell2022;40:656-73.e7 PMCID:PMC9197998

[63] Kerdidani D,Verrou KM.Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts.J Exp Med2022;219:e20210815 PMCID:PMC8764966

[64] Song J,Liu C.Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response.Nat Commun2025;16:2175 PMCID:PMC11880398

[65] Zhang X,Liu B.Single-cell RNA sequencing and spatial transcriptomics reveal the heterogeneity and intercellular communication of cancer-associated fibroblasts in gastric cancer.J Transl Med2025;23:344 PMCID:PMC11917039

[66] Bartoschek M,Bocci M.Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing.Nat Commun2018;9:5150 PMCID:PMC6279758

[67] Su S,Yao H.CD10⁺GPR77⁺ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness.Cell2018;172:841-56.e16

[68] Miyazaki Y,Inagaki Y.Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model.Sci Rep2021;11:4690 PMCID:PMC7907195

[69] Bhattacharjee S,Ravichandra A.Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts.J Clin Invest2021;131:146987 PMCID:PMC8159701

[70] Grout JA,Leader AM.Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors.Cancer Discov2022;12:2606-25 PMCID:PMC9633420

[71] Hanley CJ,Ellis MJ.Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.Nat Commun2023;14:387 PMCID:PMC9889778

[72] Xu K,Zou YX.Distinct fibroblast subpopulations associated with bone, brain or intrapulmonary metastasis in advanced non-small-cell lung cancer.Clin Transl Med2024;14:e1605 PMCID:PMC10915739

[73] Zhou X,Zuo A.THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer.Mol Cancer2024;23:282 PMCID:PMC11681647

[74] Chen Z,Liu L.Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma.Nat Commun2020;11:5077 PMCID:PMC7545162

[75] Davidson S,Riedel A.Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth.Cell Rep2020;31:107628 PMCID:PMC7242909

[76] Broz MT,Ishaya K.Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas.Nat Commun2024;15:2498 PMCID:PMC10954767

[77] Bernard V,Huang J.Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression.Clin Cancer Res2019;25:2194-205 PMCID:PMC6445737

[78] Friedman G,David E.Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4⁺ and PDPN⁺ CAFs to clinical outcome.Nat Cancer2020;1:692-708 PMCID:PMC7617059

[79] Xing X,Huang Q.Decoding the multicellular ecosystem of lung adenocarcinoma manifested as pulmonary subsolid nodules by single-cell RNA sequencing.Sci Adv2021;7:eabd9738 PMCID:PMC7840134

[80] LeBleu VS.A peek into cancer-associated fibroblasts: origins, functions and translational impact.Dis Model Mech2018;11:dmm029447 PMCID:PMC5963854

[81] Niu N,Wang Z.Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.Cancer Cell2024;42:869-84.e9

[82] Cumming J,Dongre M.Dissecting FAP+ cell diversity in pancreatic cancer uncovers an interferon-response subtype of cancer-associated fibroblasts with tumor-restraining properties.Cancer Res2025;85:2388-411 PMCID:PMC12214878

[83] Ni C,Yao X.ZIP1⁺ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn²⁺ transfer.Nat Commun2022;13:5919 PMCID:PMC9547061

[84] Mizutani Y,Iida T.Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis.Cancer Res2019;79:5367-81

[85] Iida T,Esaki N.Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics.Oncogene2022;41:2764-77

[86] Miyai Y,Hase T.Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade.Life Sci Alliance2022;5:e202101230 PMCID:PMC8897596

[87] Hutton C,Blanco-Gomez A.Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity.Cancer Cell2021;39:1227-44.e20 PMCID:PMC8443274

[88] Zhang D,Liang QY.ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer.Oncogene2023;42:2841-53 PMCID:PMC10504082

[89] Chen JH,Bamodu OA.Ovatodiolide suppresses oral cancer malignancy by down-regulating exosomal Mir-21/STAT3/β-Catenin Cargo and preventing oncogenic transformation of normal gingival fibroblasts.Cancers2019;12:56 PMCID:PMC7017298

[90] Kwon OH,Baek SJ.Aberrant upregulation of ASCL2 by promoter demethylation promotes the growth and resistance to 5-fluorouracil of gastric cancer cells.Cancer Sci2013;104:391-7 PMCID:PMC7657231

[91] Zhang H,Yue J.Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFβ1 signaling loop in esophageal squamous cell carcinoma.Mol Carcinog2017;56:1150-63

[92] Valenti G,Heynen GJJE.Cancer stem cells regulate cancer-associated fibroblasts via activation of hedgehog signaling in mammary gland tumors.Cancer Res2017;77:2134-47

[93] Kinugasa Y,Takakura N.CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment.Stem Cells2014;32:145-56

[94] Fang Y,Wang J.Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling.NPJ Precis Oncol2024;8:7 PMCID:PMC10774407

[95] Liu Q,Li G.Cancer stem cells and their niche in cancer progression and therapy.Cancer Cell Int2023;23:305 PMCID:PMC10693166

[96] Dzobo K,Dandara C.The tumor microenvironment in tumorigenesis and therapy resistance revisited.Cancers2023;15:376 PMCID:PMC9856874

[97] Dangi-Garimella S,Barron MR.Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2.Cancer Res2011;71:1019-28 PMCID:PMC3076124

[98] Begum A,Jung C.The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma.PLoS One2017;12:e0180181 PMCID:PMC5503247

[99] Li C,Liu X.Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling.Signal Transduct Target Ther2023;8:247 PMCID:PMC10300038

[100] Li Y,Xiong S.Cancer-associated fibroblasts promote the stemness of CD24⁺ liver cells via paracrine signaling.J Mol Med2019;97:243-55

[101] Fisher ML,Hwangbo Y.Cancer-associated fibroblasts promote cancer stemness by inducing expression of the chromatin-modifying protein CBX4 in squamous cell carcinoma.Carcinogenesis2023;44:485-96 PMCID:PMC10436759

[102] Liang T,Wu K.Cancer-associated fibroblast-induced remodeling of tumor microenvironment in recurrent bladder cancer.Adv Sci2023;10:e2303230 PMCID:PMC10625065

[103] Chen WJ,Chang YL.Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling.Nat Commun2014;5:3472

[104] Vaziri N,Zarrabi A,Haghjooy Javanmard S.Cancer-associated fibroblasts regulate the plasticity of breast cancer stemness through the production of leukemia inhibitory factor.Life2021;11:1298 PMCID:PMC8706708

[105] Nallasamy P,Karmakar S.Pancreatic tumor microenvironment factor promotes cancer stemness via SPP1-CD44 axis.Gastroenterology2021;161:1998-2013.e7 PMCID:PMC10069715

[106] Bai S,Chen W.The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma.J Transl Med2023;21:236 PMCID:PMC10067215

[107] Hu C,Zhang X.circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis.Mol Cancer2022;21:24 PMCID:PMC8767726

[108] Song M,Pan QZ.Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression.Hepatology2021;73:1717-35

[109] Ren J,Iaria J.Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression.Breast Cancer Res2019;21:109 PMCID:PMC6751614

[110] McAndrews KM,Kwak C.αSMA⁺ fibroblasts suppress Lgr5⁺ cancer stem cells and restrain colorectal cancer progression.Oncogene2021;40:4440-52 PMCID:PMC9150816

[111] Ou Z,Chen X.Hypoxia-induced senescent fibroblasts secrete IGF1 to promote cancer stemness in esophageal squamous cell carcinoma.Cancer Res2025;85:1064-81

[112] Donnarumma E,Nappa M.Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer.Oncotarget2017;8:19592-608 PMCID:PMC5386708

[113] Hu JL,Lan XL.CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer.Mol Cancer2019;18:91 PMCID:PMC6503554

[114] Zhuang J,Li M.Cancer-associated fibroblast-derived miR-146a-5p generates a niche that promotes bladder cancer stemness and chemoresistance.Cancer Res2023;83:1611-27

[115] Su Z,Zhang F.Cancer-associated fibroblasts-secreted exosomal miR-92a-3p promotes tumor growth and stemness in hepatocellular carcinoma through activation of Wnt/β-catenin signaling pathway by suppressing AXIN1.J Cell Physiol2024;239:e31344

[116] Ding M,Chen X.Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p.Cell Death Discov2022;8:439 PMCID:PMC9626570

[117] Ren J,Zhang D.Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19.Theranostics2018;8:3932-48 PMCID:PMC6071523

[118] Yang L,Yeung TL.Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth.Cell Metab2016;24:685-700 PMCID:PMC7329194

[119] Achreja A,Yang L,Marini J.Exo-MFA - A 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism.Metab Eng2017;43:156-72 PMCID:PMC7393794

[120] Sousa CM,Wang X.Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.Nature2016;536:479-83 PMCID:PMC5228623

[121] Yu S,Su A.A CD10-OGP membrane peptolytic signaling axis in fibroblasts regulates lipid metabolism of cancer stem cells via SCD1.Adv Sci2021;8:e2101848 PMCID:PMC8498877

[122] Fan G,Tang L.TSPAN8⁺ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.Sci Transl Med2024;16:eadj5705

[123] Lewinska M,Satriano L.Fibroblast-derived lysyl oxidase increases oxidative phosphorylation and stemness in cholangiocarcinoma.Gastroenterology2024;166:886-901.e7

[124] Zhang S,Ouyang Y,Hu L.Cancer stem cells: a target for overcoming therapeutic resistance and relapse.Cancer Biol Med2024;20:985-1020 PMCID:PMC10845928

[125] Hofheinz RD,Hartmann F.Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer.Onkologie2003;26:44-8

[126] Narra K,Lee HO.Phase II trial of single agent Val-boroPro (Talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer.Cancer Biol Ther2007;6:1691-9

[127] Elboga U,Kus T.Superiority of ⁶⁸Ga-FAPI PET/CT scan in detecting additional lesions compared to ¹⁸FDG PET/CT scan in breast cancer.Ann Nucl Med2021;35:1321-31

[128] Dendl K,Finck R.⁶⁸Ga-FAPI-PET/CT in patients with various gynecological malignancies.Eur J Nucl Med Mol Imaging2021;48:4089-100 PMCID:PMC8484099

[129] Zboralski D,Bredenbeck A.Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy.Eur J Nucl Med Mol Imaging2022;49:3651-67 PMCID:PMC9399058

[130] Ariga N,Ohuchi N,Ohtani H.Stromal expression of fibroblast activation protein/seprase, a cell membrane serine proteinase and gelatinase, is associated with longer survival in patients with invasive ductal carcinoma of breast.Int J Cancer2001;95:67-72

[131] Wu Z,Tang R.The role of PDGFRA in predicting oncological and immune characteristics in pancreatic ductal adenocarcinoma.J Oncol2022;2022:4148805 PMCID:PMC8976608

[132] Choi SY,Lee SJ.Podoplanin, α-smooth muscle actin or S100A4 expressing cancer-associated fibroblasts are associated with different prognosis in colorectal cancers.J Korean Med Sci2013;28:1293-301 PMCID:PMC3763102

[133] Takahashi A,Neri S.Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth.Oncotarget2015;6:9531-41 PMCID:PMC4496236

[134] Chen Y,Kalluri R.Clinical and therapeutic relevance of cancer-associated fibroblasts.Nat Rev Clin Oncol2021;18:792-804 PMCID:PMC8791784

[135] Catenacci DV,Karrison T.Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer.J Clin Oncol2015;33:4284-92 PMCID:PMC4678179

[136] Ko AH,Tempero MA.A phase I study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma.Pancreas2016;45:370-5 PMCID:PMC5908466

[137] Ramanathan RK,Philip PA.Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313.J Clin Oncol2019;37:1062-9 PMCID:PMC6494359

[138] Van Cutsem E, Tempero MA, Sigal D, et al.; HALO 109-301 Investigators. Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma.J Clin Oncol2020;38:3185-94 PMCID:PMC7499614

[139] Huang TX,Fu L.Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells.Am J Cancer Res2019;9:1889-904 PMCID:PMC6780671

[140] Greco R,Qu H.Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade.Oncoimmunology2020;9:1811605 PMCID:PMC7657645

[141] Burvenich IJG,Guo N.Radiolabelling and preclinical characterization of ⁸⁹Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa.Eur J Nucl Med Mol Imaging2021;48:3075-88

[142] Cheng B,Chen P.Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer.Cancer Commun2022;42:17-36 PMCID:PMC8753312

[143] Steele NG,Kemp SB.Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer.Clin Cancer Res2021;27:2023-37 PMCID:PMC8026631

[144] Wong H,West KA.Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation.Clin Cancer Res2011;17:4682-92

[145] Lewis K,Farberg AS,Squittieri N.Effects of sonidegib following dose reduction and treatment interruption in patients with advanced basal cell carcinoma during 42-month BOLT trial.Dermatol Ther2021;11:2225-34 PMCID:PMC8611137

[146] Kim EJ,Abel EV.Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma.Clin Cancer Res2014;20:5937-45 PMCID:PMC4254161

[147] Catenacci DVT,Davidenko I.Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol2017;18:1467-82 PMCID:PMC5898242

[148] He J,Wang S.Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer.Cancer Lett2025;631:217917

[149] Zhao ZX,Sun H.Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling.Acta Pharmacol Sin2023;44:178-88 PMCID:PMC9813133

[150] Gorchs L,Mayer C.The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity.Sci Rep2020;10:17444 PMCID:PMC7562723

[151] Ng K,McCleary NJ.Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: the SUNSHINE randomized clinical trial.JAMA2019;321:1370-9 PMCID:PMC6459117

[152] Lee PJ,Ho H.Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts.Theranostics2021;11:9667-86 PMCID:PMC8490509

[153] Cazet AS,Elsworth BL.Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.Nat Commun2018;9:2897 PMCID:PMC6057940

[154] Sajeev A,Unnikrishnan J.Unlocking the potential of Berberine: advancing cancer therapy through chemosensitization and combination treatments.Cancer Lett2024;597:217019

[155] Ai F,Yu B et al.Berberine regulates proliferation, collagen synthesis and cytokine secretion of cardiac fibroblasts via AMPK-mTOR-p70S6K signaling pathway.Int J Clin Exp Pathol2015;8:12509-16 PMCID:PMC4680383

[156] Xu N,Wang W.Anti-tumor therapy of glycyrrhetinic acid targeted liposome co-delivery of doxorubicin and berberine for hepatocellular carcinoma.Drug Deliv Transl Res2024;14:2386-402

[157] Ibrahim N,Yasavoli-Sharahi H.Berberine inhibits breast cancer stem cell development and decreases inflammation: involvement of miRNAs and IL-6.Curr Dev Nutr2025;9:104532 PMCID:PMC11786844

[158] Ma YY,Liu PF.Comprehensive genomic analysis of puerarin in inhibiting bladder urothelial carcinoma cell proliferation and migration.Recent Pat Anticancer Drug Discov2024;19:516-29 PMCID:PMC11348475

[159] Guo J,Huang Z.Puerarin decreases the expression of FUS-dependent MAPK4 to inhibit the development of triple-negative breast cancer.Chem Biol Drug Des2024;104:e14617

[160] Liu Y,Chen J.An injectable puerarin depot can potentiate chimeric antigen receptor natural killer cell immunotherapy against targeted solid tumors by reversing tumor immunosuppression.Small2024;20:e2307521

[161] Miao L,Lin CM.Nanoparticle modulation of the tumor microenvironment enhances therapeutic efficacy of cisplatin.J Control Release2015;217:27-41 PMCID:PMC4623876

[162] Xu H,Liu M.Nano-puerarin regulates tumor microenvironment and facilitates chemo- and immunotherapy in murine triple negative breast cancer model.Biomaterials2020;235:119769 PMCID:PMC7093100

[163] Tao X,Lian D.Puerarin 6″-O-xyloside suppresses growth, self-renewal and invasion of lung cancer stem-like cells derived from A549 cells via regulating Akt/c-Myc signalling.Clin Exp Pharmacol Physiol2020;47:1311-9

[164] Wu C,Jiang S.Cinnamaldehyde induces apoptosis and reverses epithelial-mesenchymal transition through inhibition of Wnt/β-catenin pathway in non-small cell lung cancer.Int J Biochem Cell Biol2017;84:58-74

[165] Han L,Ma J.Cinnamaldehyde induces endogenous apoptosis of the prostate cancer-associated fibroblasts via interfering the Glutathione-associated mitochondria function.Med Oncol2020;37:91

[166] Zeng Y,Zhang Z.Curcumin promotes cancer-associated fibroblasts apoptosis via ROS-mediated endoplasmic reticulum stress.Arch Biochem Biophys2020;694:108613

[167] Khan S,Kumari S.Superparamagnetic iron oxide nanoparticles of curcumin enhance gemcitabine therapeutic response in pancreatic cancer.Biomaterials2019;208:83-97

[168] Sun L,Wang L.Resolvin D1 prevents epithelial-mesenchymal transition and reduces the stemness features of hepatocellular carcinoma by inhibiting paracrine of cancer-associated fibroblast-derived COMP.J Exp Clin Cancer Res2019;38:170 PMCID:PMC6472102

[169] Dauer P,Gupta VK.Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression.Cancer Res2018;78:1321-33 PMCID:PMC5935584

[170] Rodriguez-Blanco J,Suter RK.Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models.J Clin Invest2024;134:e171136 PMCID:PMC11290968

[171] Nomura A,Dudeja V,Saluja AK.Minnelide effectively eliminates CD133⁺ side population in pancreatic cancer.Mol Cancer2015;14:200 PMCID:PMC4657383

[172] Koksalar Alkan F,Alkan HK.Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.Sci Rep2024;14:22487 PMCID:PMC11439009

[173] Lim SH,Vickers S.The safety and efficacy outcomes of Minnelide given alone or in combination with paclitaxel in advanced gastric cancer: a phase I trial.Cancer Lett2024;597:217041

[174] Wang X.Highlights the recent important findings in cancer heterogeneity.Holist Integ Oncol2023;2:15

[175] Tong T,Jian H.The role and potential mechanisms of exosomes in the progression of hepatocellular carcinoma.Holist Integ Oncol2025;4:36