Zou, A. E., Kongthong, S., Mueller, A. A. & Brenner, M. B. Fibroblasts in immune responses, inflammatory diseases and therapeutic implications. Nat. Rev. Rheumatol. 21, 336–354 (2025).
Google ScholarÂ
Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).
Google ScholarÂ
Buechler, M. B. & Turley, S. J. A short field guide to fibroblast function in immunity. Semin. Immunol. 35, 48–58 (2018).
Google ScholarÂ
Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730 (2019).
Google ScholarÂ
Farbehi, N. et al. Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury. eLife 8, e43882 (2019).
Google ScholarÂ
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Google ScholarÂ
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Google ScholarÂ
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Google ScholarÂ
Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).
Google ScholarÂ
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154 (2022).
Google ScholarÂ
Lakins, M. A., Ghorani, E., Munir, H., Martins, C. P. & Shields, J. D. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T cells to protect tumour cells. Nat. Commun. 9, 948 (2018).
Google ScholarÂ
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Google ScholarÂ
Chen, S. et al. Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway. Int. J. Oncol. 59, 59 (2021).
Google ScholarÂ
Mayer, S. et al. The tumor microenvironment shows a hierarchy of cell–cell interactions dominated by fibroblasts. Nat. Commun. 14, 5810 (2023).
Google ScholarÂ
Ershaid, N. et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat. Commun. 10, 4375 (2019).
Google ScholarÂ
Xiang, H. et al. Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma. Cancer Immunol. Res. 8, 436–450 (2020).
Google ScholarÂ
Walch-Rückheim, B. et al. Cervical cancer-instructed stromal fibroblasts enhance IL-23 expression in dendritic cells to support expansion of TH17 cells. Cancer Res. 79, 1573–1586 (2019).
Google ScholarÂ
Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2020).
Google ScholarÂ
Ben-Shmuel, A. et al. Cancer-associated fibroblasts serve as decoys to suppress NK cell anticancer cytotoxicity in breast cancer. Cancer Discov. 15, 1247–1269 (2025).
Google ScholarÂ
Ye, J. et al. Senescent CAFs mediate immunosuppression and drive breast cancer progression. Cancer Discov. 14, 1302–1323 (2024).
Google ScholarÂ
Arpinati, L. & Scherz-Shouval, R. From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts. Trends Cancer 9, 421–443 (2023).
Google ScholarÂ
Hutton, C. et al. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 39, 1227–1244 (2021).
Google ScholarÂ
Helms, E. J. et al. Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts. Cancer Discov. 12, 484–501 (2022).
Google ScholarÂ
Qiu, W. et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 40, 650–655 (2008).
Google ScholarÂ
Gavish, A. et al. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours. Nature 618, 598–606 (2023).
Google ScholarÂ
Black, J. R. M. & McGranahan, N. Genetic and non-genetic clonal diversity in cancer evolution. Nat. Rev. Cancer 21, 379–392 (2021).
Google ScholarÂ
Li, Z., Seehawer, M. & Polyak, K. Untangling the web of intratumour heterogeneity. Nat. Cell Biol. 24, 1192–1201 (2022).
Google ScholarÂ
McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).
Google ScholarÂ
Jin, S. et al. Inference and analysis of cell–cell communication using CellChat. Nat. Commun. 12, 1088 (2021).
Google ScholarÂ
Troulé, K. et al. CellPhoneDB v5: inferring cell–cell communication from single-cell multiomics data. Nat. Protoc. 20, 3412–3440 (2025).
Google ScholarÂ
Surwase, S. S. et al. Highly multiplexed immunofluorescence PhenoCycler panel for murine formalin-fixed paraffin-embedded tissues yields insight into tumor microenvironment immunoengineering. Lab. Invest. 105, 102165 (2025).
Google ScholarÂ
Agorku, D. J., Bosio, A., Alves, F., Ströbel, P. & Hardt, O. Colorectal cancer-associated fibroblasts inhibit effector T cells via NECTIN2 signaling. Cancer Lett. 595, 216985 (2024).
Liu, Y. et al. Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics. Cancer Cell 43, 905–924 (2025).
Google ScholarÂ
Oliveira, M. F. et al. High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer. Nat. Genet. 57, 1512–1523 (2025).
Google ScholarÂ
Ma, C. et al. Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment. Mol. Cancer 22, 170 (2023).
Google ScholarÂ
Gao, Y. et al. Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation. Cancer Cell 42, 1764–1783 (2024).
Google ScholarÂ
Cords, L. et al. Cancer-associated fibroblast classification in single-cell and spatial proteomics data. Nat. Commun. 14, 4294 (2023).
Google ScholarÂ
Du, Y. et al. Integration of pan-cancer single-cell and spatial transcriptomics reveals stromal cell features and therapeutic targets in tumor microenvironment. Cancer Res. 84, 192–210 (2024).
Google ScholarÂ
Jenkins, B. H. et al. Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response. Mol. Cancer 24, 3 (2025).
Google ScholarÂ
Kato, T. et al. Cancer-associated fibroblasts affect intratumoral CD8+ and FoxP3+ T cells via IL-6 in the tumor microenvironment. Clin. Cancer Res. 24, 4820–4833 (2018).
Google ScholarÂ
Hu, G. et al. An IL-6-adenosine positive feedback loop between CD73+ γδTregs and CAFs promotes tumor progression in human breast cancer. Cancer Immunol. Res. 8, 1273–1286 (2020).
Google ScholarÂ
Kitamura, F. et al. Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer. JCI Insight 8, e163022 (2023).
Google ScholarÂ
Erez, N., Truitt, M., Olson, P., Arron, S. T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010).
Google ScholarÂ
Cao, M. et al. PPY-induced iCAFs cultivate an immunosuppressive microenvironment in pancreatic cancer. Adv. Sci. 12, e2413432 (2025).
Google ScholarÂ
Huang, H. et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 40, 656–673 (2022).
Google ScholarÂ
Song, J. et al. Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response. Nat. Commun. 16, 2175 (2025).
Google ScholarÂ
Chen, X. et al. Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches. Cancer Cell 43, 2224–2240 (2025).
Thiel, V. et al. Characterization of single neurons reprogrammed by pancreatic cancer. Nature 640, 1042–1051 (2025).
Google ScholarÂ
van Baarle, L. et al. IL-1R signaling drives enteric glia–macrophage interactions in colorectal cancer. Nat. Commun. 15, 6079 (2024).
Google ScholarÂ
Zhou, Y., Li, J., Han, B., Zhong, R. & Zhong, H. Schwann cells promote lung cancer proliferation by promoting the M2 polarization of macrophages. Cell. Immunol. 357, 104211 (2020).
Google ScholarÂ
Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022).
Google ScholarÂ
Xue, M. et al. Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment. Nat. Commun. 14, 3742 (2023).
Google ScholarÂ
Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2020).
Google ScholarÂ
Carpenter, E. S. et al. Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions. Cancer Discov. 13, 1324–1345 (2023).
Google ScholarÂ
Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 5, e129212 (2019).
Google ScholarÂ
Chhabra, Y. & Weeraratna, A. T. Fibroblasts in cancer: unity in heterogeneity. Cell 186, 1580–1609 (2023).
Google ScholarÂ
Helms, E., Onate, M. K. & Sherman, M. H. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov. 10, 648–656 (2020).
Google ScholarÂ
Neuzillet, C. et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J. Pathol. 248, 51–65 (2019).
Google ScholarÂ
Carpenter, E. S. et al. Pancreatic cancer-associated fibroblasts: where do we go from here? Cancer Res. 84, 3505–3508 (2024).
Google ScholarÂ
Biffi, G. et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).
Google ScholarÂ
Izar, B. et al. A single-cell landscape of high-grade serous ovarian cancer. Nat. Med. 26, 1271–1279 (2020).
Google ScholarÂ
Zhang, M. et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J. Hepatol. 73, 1118–1130 (2020).
Google ScholarÂ
Sebastian, A. et al. Single-cell transcriptomic analysis of tumor-derived fibroblasts and normal tissue-resident fibroblasts reveals fibroblast heterogeneity in breast cancer. Cancers 12, 1307 (2020).
Google ScholarÂ
Yang, W., Zhang, S., Li, T., Zhou, Z. & Pan, J. Single-cell analysis reveals that cancer-associated fibroblasts stimulate oral squamous cell carcinoma invasion via the TGF-β/Smad pathway. Acta Biochim. Biophys. 55, 262–273 (2022).
Foster, D. S. et al. Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer Cell 40, 1392–1406 (2022).
Google ScholarÂ
Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).
Google ScholarÂ
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
Google ScholarÂ
Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815. (2022).
Google ScholarÂ
Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).
Google ScholarÂ
Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).
Google ScholarÂ
Liu, C. et al. Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression. Sci. Adv. 9, eadd8977 (2023).
Google ScholarÂ
Belle, J. I. et al. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov. 14, 1324–1355 (2024).
Google ScholarÂ
Wang, Y. et al. Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response. Cell Discov. 7, 36 (2021).
Google ScholarÂ
Wu, C. et al. Metabolic-suppressed cancer-associated fibroblasts limit the immune environment and survival in colorectal cancer with liver metastasis. Front. Pharmacol. 14, 1212420 (2023).
Google ScholarÂ
Iwamoto, C. et al. Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Cancer Lett. 512, 15–27 (2021).
Google ScholarÂ
Weber, C. E. et al. Osteopontin mediates an MZF1–TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene 34, 4821–4833 (2015).
Google ScholarÂ
Hosaka, K. et al. Pericyte–fibroblast transition promotes tumor growth and metastasis. Proc. Natl Acad. Sci. USA 113, E5618–E5627 (2016).
Google ScholarÂ
Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).
Google ScholarÂ
Garcia, P. E. et al. Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma. Cell. Mol. Gastroenterol. Hepatol. 10, 581–599 (2020).
Google ScholarÂ
Affo, S. et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 866–882 (2021).
Google ScholarÂ
Rinkevich, Y. et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015).
Google ScholarÂ
Wang, S.-S. et al. Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis. J. Exp. Med. 222, e20232123 (2025).
Google ScholarÂ
Lior, C. et al. Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response. Cell Rep. 43, 114236 (2024).
Google ScholarÂ
Sandoval, P. et al. Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis. J. Pathol. 231, 517–531 (2013).
Google ScholarÂ
Tomero-Sanz, H. et al. Detection of carcinoma-associated fibroblasts derived from mesothelial cells via mesothelial-to-mesenchymal transition in primary ovarian carcinomas. Cancers 16, 2697 (2024).
Google ScholarÂ
Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).
Google ScholarÂ
Saito, K. et al. Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction. J. Cancer 9, 2916–2929 (2018).
Google ScholarÂ
Barcellos-de-Souza, P. et al. Mesenchymal stem cells are recruited and activated into carcinoma-associated fibroblasts by prostate cancer microenvironment-derived TGF-β1. Stem Cells 34, 2536–2547 (2016).
Google ScholarÂ
Bochet, L. et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 73, 5657–5668 (2013).
Google ScholarÂ
Kurashige, M. et al. Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation. Commun. Biol. 1, 131 (2018).
Google ScholarÂ
Worthley, D. L. et al. Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cells 27, 1463–1468 (2009).
Google ScholarÂ
Mucciolo, G. et al. EGFR-activated myofibroblasts promote metastasis of pancreatic cancer. Cancer Cell 42, 101–118 (2024).
Google ScholarÂ
Lee, H. O. et al. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer 11, 245 (2011).
Google ScholarÂ
Cumming, J. et al. Dissecting FAP+ cell diversity in pancreatic cancer uncovers an interferon-response subtype of cancer-associated fibroblasts with tumor-restraining properties. Cancer Res. 85, 2388–2411 (2025).
Google ScholarÂ
Croizer, H. et al. Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer. Nat. Commun. 15, 2806 (2024).
Google ScholarÂ
Xiao, Z. et al. Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat. Commun. 14, 5110 (2023).
Google ScholarÂ
Yang, X. et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3–CCL2 signaling. Cancer Res. 76, 4124–4135 (2016).
Google ScholarÂ
Cremasco, V. et al. FAP delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol. Res. 6, 1472–1485 (2018).
Google ScholarÂ
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479 (2018).
Google ScholarÂ
Shaashua, L. et al. BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling. Nat. Commun. 13, 6513 (2022).
Google ScholarÂ
Francescone, R. et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 11, 446–479 (2021).
Google ScholarÂ
Han, C., Liu, T. & Yin, R. Biomarkers for cancer-associated fibroblasts. Biomark. Res. 8, 64 (2020).
Google ScholarÂ
Tsukamoto, S. et al. Podoplanin expression in early-stage colorectal cancer-associated fibroblasts and its utility as a diagnostic marker for colorectal lesions. Cells 13, 1682 (2024).
Google ScholarÂ
Hogervorst, M., Rietveld, M., de Gruijl, F. & El Ghalbzouri, A. A shift from papillary to reticular fibroblasts enables tumour-stroma interaction and invasion. Br. J. Cancer 118, 1089–1097 (2018).
Google ScholarÂ
Breiteneder-Geleff, S. et al. Podoplanin—a specific marker for lymphatic endothelium expressed in angiosarcoma. Verh. Dtsch. Ges. Pathol. 83, 270–275 (1999).
Google ScholarÂ
Broz, M. T. et al. Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas. Nat. Commun. 15, 2498 (2024).
Google ScholarÂ
Han, L. et al. The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis. Nat. Commun. 14, 1 (2023).
Google ScholarÂ
Paulsson, J. et al. Prognostic significance of stromal platelet-derived growth factor β-receptor expression in human breast cancer. Am. J. Pathol. 175, 334–341 (2009).
Google ScholarÂ
Micke, P. & Ostman, A. Tumour–stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45, S163–S175 (2004).
Google ScholarÂ
McAndrews, K. M. et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL-6-mediated therapy resistance in pancreatic cancer. Cancer Discov. 12, 1580–1597 (2022).
Google ScholarÂ
Pei, G. et al. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature 642, 212–221 (2025).
Google ScholarÂ
Veghini, L. et al. Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer. Nat. Commun. 15, 10534 (2024).
Google ScholarÂ
Vennin, C. et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat. Commun. 10, 3637 (2019).
Google ScholarÂ
Schworer, S. et al. Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines. Cancer Res. 83, 1596–1610 (2023).
Google ScholarÂ
Garcia Garcia, C. J. et al. Stromal HIF2 regulates immune suppression in the pancreatic cancer microenvironment. Gastroenterology 162, 2018–2031 (2022).
Google ScholarÂ
Zhang, Y. et al. Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer. Cancer Cell 43, 1677–1696 (2025).
Google ScholarÂ
Erez, N. Location, location: understanding the metastatic microenvironment. Mol. Oncol. 17, 1695–1698 (2023).
Google ScholarÂ
Gui, Y. et al. Metastatic breast carcinoma-associated fibroblasts have enhanced protumorigenic properties related to increased IGF2 expression. Clin. Cancer Res. 25, 7229–7242 (2019).
Google ScholarÂ
Shen, Y. et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell 37, 800–817 (2020).
Google ScholarÂ
Steele, N. G. et al. Primary and metastatic cellular landscapes in human pancreatic cancer. iScience 28, 113012 (2025).
Google ScholarÂ
Castano, Z. et al. Stromal EGF and IGF-I together modulate plasticity of disseminated triple-negative breast tumors. Cancer Discov. 3, 922–935 (2013).
Google ScholarÂ
Ji, Q. et al. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nat. Commun. 11, 1211 (2020).
Google ScholarÂ
Chung, B. et al. Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12. npj Breast Cancer 3, 6 (2017).
Google ScholarÂ
Cheng, P. S. W., Zaccaria, M. & Biffi, G. Functional heterogeneity of fibroblasts in primary tumors and metastases. Trends Cancer 11, 135–153 (2025).
Google ScholarÂ
Raz, Y. et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J. Exp. Med. 215, 3075–3093 (2018).
Google ScholarÂ
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
Google ScholarÂ
Wang, Z. et al. Metastasis-associated fibroblasts: an emerging target for metastatic cancer. Biomark. Res. 9, 47 (2021).
Google ScholarÂ
de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).
Google ScholarÂ
Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
Google ScholarÂ
Ao, Z. et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 75, 4681–4687 (2015).
Google ScholarÂ
Wintzell, M., Hjerpe, E., Avall Lundqvist, E. & Shoshan, M. Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites. BMC Cancer 12, 359 (2012).
Google ScholarÂ
Duda, D. G. et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl Acad. Sci. USA 107, 21677–21682 (2010).
Google ScholarÂ
Kaur, A. et al. Corrigendum: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 537, 254 (2016).
Google ScholarÂ
Zabransky, D. J. et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 84, 1221–1236 (2024).
Google ScholarÂ
Seo, B. R. et al. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci. Transl. Med. 7, 301ra130 (2015).
Google ScholarÂ
Kim, T.-Y. et al. A high-fat diet activates the BAs–FXR axis and triggers cancer-associated fibroblast properties in the colon. Cell. Mol. Gastroenterol. Hepatol. 13, 1141–1159 (2022).
Google ScholarÂ
Chen, G. et al. Bridging the tumor microenvironment: the pivotal role of cancer-associated fibroblasts in tumor cachexia development. Mol. Cancer 24, 194 (2025).
Google ScholarÂ
Teicher, B. A. et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247, 1457–1461 (1990).
Google ScholarÂ
Shekhar, M. P. V., Santner, S., Carolin, K. A. & Tait, L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am. J. Pathol. 170, 1546–1560 (2007).
Google ScholarÂ
Wang, W. et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 15, 6630–6638 (2009).
Google ScholarÂ
McMillin, D. W. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med. 16, 483–489 (2010).
Google ScholarÂ
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
Google ScholarÂ
Cazet, A. S. et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat. Commun. 9, 2897 (2018).
Google ScholarÂ
Hu, H. et al. Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms. Cancer Cell 39, 1531–1547 (2021).
Google ScholarÂ
Zhang, Y.-P. et al. PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy. Cancer Cell 43, 856–874 (2025).
Google ScholarÂ
Hwang, W. L. et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat. Genet. 54, 1178–1191 (2022).
Google ScholarÂ
Shiau, C. et al. Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment. Nat. Genet. 56, 2466–2478 (2024).
Google ScholarÂ
Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856 (2018).
Google ScholarÂ
Fan, G. et al. TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer. Sci. Transl. Med. 16, eadj5705 (2024).
Google ScholarÂ
Wang, H. et al. Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer. Cancer Cell 41, 1345–1362 (2023).
Google ScholarÂ
Liu, X. et al. Stromal reprogramming overcomes resistance to RAS–MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy. Sci. Transl. Med. 16, eado2402 (2024).
Google ScholarÂ
Bhattacharyya, S. et al. Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer. J. Exp. Med. 217, e20191805 (2020).
Google ScholarÂ
Han, J. et al. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes Dev. 37, 818–828 (2023).
Google ScholarÂ
Lan, Y. et al. Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses. J. Immunother. Cancer 10, e004122 (2022).
Google ScholarÂ
Lan, Y. et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci. Transl. Med. 10, eaan5488 (2018).
Google ScholarÂ
Strauss, J. et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin. Cancer Res. 24, 1287–1295 (2018).
Google ScholarÂ
Paz-Ares, L. et al. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J. Thorac. Oncol. 15, 1210–1222 (2020).
Google ScholarÂ
Lan, Y. et al. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell 39, 1388–1403 (2021).
Google ScholarÂ
Kment, J. et al. Blockade of TGF-β and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses. Br. J. Cancer 130, 2003–2015 (2024).
Google ScholarÂ
Grauel, A. L. et al. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts. Nat. Commun. 11, 6315 (2020).
Google ScholarÂ
Davidson, G. et al. Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear cell renal cell carcinoma. Cancer Res. 83, 2952–2969 (2023).
Google ScholarÂ
Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).
Google ScholarÂ
Pich-Bavastro, C. et al. Activin A-mediated polarization of cancer-associated fibroblasts and macrophages confers resistance to checkpoint immunotherapy in skin cancer. Clin. Cancer Res. 29, 3498–3513 (2023).
Google ScholarÂ
Chen, X. et al. IL-17-induced HIF1α drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion. J. Exp. Med. 219, e20210693 (2022).
Google ScholarÂ
Datta, J. et al. Combined MEK and STAT3 inhibition uncovers stromal plasticity by enriching for cancer-associated fibroblasts with mesenchymal stem cell-like features to overcome immunotherapy resistance in pancreatic cancer. Gastroenterology 163, 1593–1612 (2022).
Google ScholarÂ
Desai, P. et al. Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities. Cell Rep. Med. 5, 101610 (2024).
Google ScholarÂ
Ramos Zapatero, M. et al. Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses. Cell 186, 5606–5619 (2023).
Google ScholarÂ
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
Google ScholarÂ
Özdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).
Google ScholarÂ
Blair, A. B. et al. Dual stromal targeting sensitizes pancreatic adenocarcinoma for anti-programmed cell death protein 1 therapy. Gastroenterology 163, 1267–1280 (2022).
Google ScholarÂ
Kannan, S., Lock, I., Ozenberger, B. B. & Jones, K. B. Genetic drivers and cells of origin in sarcomagenesis. J. Pathol. 254, 474–493 (2021).
Google ScholarÂ
Ding, Z. et al. Cancer-associated fibroblasts in hematologic malignancies: elucidating roles and spotlighting therapeutic targets. Front. Oncol. 13, 1193978 (2023).
Google ScholarÂ
