Classification，distribution and relationship with tumors of CAF

doi:10.3760/cma.j.cn371439-20250613-00027

Abstract

Abstract:

Cancer-associated fibroblasts （CAFs） are important components in constructing tumor microenvironment and exhibit significant heterogeneity. Currently，more than ten CAFs subtypes have been identified，which can be classified into two major categories： cancer-promoting and cancer-restraining. Cancer-promoting CAFs promotes tumor progression through extracellular matrix remodeling，immune suppression，angiogenesis and metabolic reprogramming. In contrast，cancer-restraining CAFs exerts anti-tumor effects by recruiting CD8⁺ T cells/natural killer （NK） cells. The spatial distribution of different CAFs subtypes is closely associated with the specific microenvironment of the tumor region，and multiple subtypes can undergo dynamic transformation under specific conditions，inducing tumor treatment resistance and thereby affecting patient prognosis. Targeting the elimination of cancer-promoting CAFs subsets or inducing their transformation into cancer-restraining subtypes is a promising strategy for remodeling the tumor microenvironment，inhibiting tumor progression，and overcoming drug resistance.

Key words: Cancer-associated fibroblast, Tissue distribution, Tumor escape, Metabolism

Qing Shuman, Wang Yuanyuan, Yu Shuyang, Li Yingge, Yao Yi. Classification，distribution and relationship with tumors of CAF[J]. Journal of International Oncology, 2026, 53(3): 167-173.

Figures/Tables 1

CAF亚型	缩写	特征基因	CAIX表达	标志蛋白	参与的生物学功能	空间分布
肌成纤维细胞样 CAF^[3,14-18]	myCAF	FAP、TPMI1、THBS2、 HAS2	阴性	α-SMA、POSTIN、 LRRC15、ITGA11、 SPARC	肿瘤细胞增殖、迁移、 ECM重塑	癌巢附近
基质重塑型 CAF^[11,19-21]	mCAF	MMP-11、CDH11、POSTN、 COL5A1、COL6A3、LUM、 DCN、FBLN、LOX、VCA	阴性	MMP-11、纤维蛋白-1、 Collagens、POSTIN、 LUM、DCN、FAP	基质沉积、ECM重塑、血管生成、免疫调节	肿瘤富基质边缘，临近血管、间质中表达
胞外基质型 CAF^[22-23]	eCAF	MMP-14、LOXL2、POX2、 POL4	阴性	POSTIN	免疫细胞极化、 ECM重塑	肿瘤远心部位的间质
炎症型 CAF^{[11,17-19,22]}	iCAF	CD34、CD248、C3/CFD、 CXCL12、CXCL14、IL-6、 PLA2G2A	阴性	CD26、IL-6、CXCL12、 LIF、APOD、PDGFR-α	免疫细胞浸润、化疗耐药	因癌种而异，非小细胞肺癌中多位于富癌区和氧分压正常区，胰腺癌中位于远离肿瘤细胞的结缔组织增生区
抗原呈递型 CAF^[24-27]	apCAF	CD74、HLA-DRA、ACTA2、 CCL5	阴性	MHC-Ⅱ、CDH11、 PDPN、CD74	肿瘤抗原呈递、免疫调节	间皮样apCAF临近肿瘤细胞，纤维细胞样apCAF多在淋巴细胞富集区
瘤样CAF^[4,11]	tCAF	PDPN、MME、ENO1	阳性	CD10、CD73、CAIX	肿瘤生长、血管生成	临近肿瘤-基质界面、缺氧区，与肿瘤细胞接触
缺氧 tCAF^[11]	-	-	阳性	CD10	肿瘤耐药	缺氧区或富癌区
血管相关型 CAF^[3,11,20,23]	vCAF	CD134、MACM（CD146）、 ACTA2、MEF2C、MUSTN1、 RGS5、NOTCH3	阴性	结蛋白、巢蛋白-2、 VEGF	血管生成	富癌区，临近血管
循环型CAF^[20]	cCAF	-		Ki-67		vCAF聚集区域
代谢型CAF^[28]	meCAF	PLA2G2A、KLF16、 CRABP2	-	PLA2G2A	糖酵解	基质区域，靠近mCAF
脂质加工型 CAF^[24]	lpCAF	-	-	载脂蛋白A1、载脂蛋白C1	脂质加工	瘤外分布
脂质加工基质型 CAF^[24]	lpmCAF （CD36⁺ CAF）	COL6A3、COL1A1、CD36、 STEAP4	-	CD36	ECM、胆固醇和脂肪酸代谢	瘤内分布
干扰素响应型 CAF^[11]	ifnCAF	IL-32、CXCL9、CXCL 10、 CXCL11、IDO1	阴性	IDO	慢性炎症	肿瘤-基质界面
SMA型CAF^[11]	SMA-CAF	-	阴性	SMA、PDGFR-b、 CD146、FAP（-）、 MMP（-）、Collagen（-）	免疫细胞浸润	基质区
发育型 CAF^[3,11,20,23]	dCAF	SCRG1、MKI67、TUBA1B、 SOX9、SOX10	阴性	SCRG1、Ki-67	细胞分裂	肿瘤-基质界面

References 56

[1]	Tsoumakidou M. The advent of immune stimulating CAFs in cancer[J]. Nat Rev Cancer, 2023, 23(4): 258-269. DOI: 10.1038/s41568-023-00549-7. pmid: 36807417
[2]	Kanzaki R, Pietras K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine[J]. Cancer Sci, 2020, 111(8): 2708-2717. DOI: 10.1111/cas.14537.
[3]	Mao X, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives[J]. Mol Cancer, 2021, 20(1): 131. DOI: 10.1186/s12943-021-01428-1. pmid: 34635121
[4]	Cords L, Tietscher S, Anzeneder T, et al. Cancer-associated fibroblast classification in single-cell and spatial proteomics data[J]. Nat Commun, 2023, 14(1): 4294. DOI: 10.1038/s41467-023-39762-1. pmid: 37463917
[5]	Coursier D, Calvo F. CAFs vs. TECs: when blood feuds fuel cancer progression, dissemination and therapeutic resistance[J]. Cell Oncol (Dordr), 2024, 47(4): 1091-1112. DOI: 10.1007/s13402-024-00931-z. pmid: 38453816
[6]	Tian TV, Affò S. Stromal barriers to the abscopal effect[J]. Cancer Cell, 2025, 43(5): 810-812. DOI: 10.1016/j.ccell.2025.04.008. pmid: 40359907
[7]	王文浩, 孙希瑞, 刘锦, 等. 肿瘤相关成纤维细胞在乳腺癌发生与发展中的作用[J]. 国际肿瘤学杂志, 2022, 49(10): 615-618. DOI: 10.3760/cma.j.cn371439-20220614-00122.
[8]	Li L, Wei JR, Dong J, et al. Laminin γ2-mediating T cell exclusion attenuates response to anti-PD-1 therapy[J]. Sci Adv, 2021, 7(6): eabc8346. DOI: 10.1126/sciadv.abc8346.
[9]	Li C, Teixeira AF, Zhu HJ, et al. Cancer associated-fibroblast-derived exosomes in cancer progression[J]. Mol Cancer, 2021, 20(1): 154. DOI: 10.1186/s12943-021-01463-y. pmid: 34852849
[10]	Lin Z, Li G, Jiang K, et al. Cancer therapy resistance mediated by cancer-associated fibroblast-derived extracellular vesicles: biological mechanisms to clinical significance and implications[J]. Mol Cancer, 2024, 23(1): 191. DOI: 10.1186/s12943-024-02106-8. pmid: 39244548
[11]	Cords L, Engler S, Haberecker M, et al. Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer[J]. Cancer Cell, 2024, 42(3): 396-412.e5. DOI: 10.1016/j.ccell.2023.12.021.
[12]	Miyai Y, Esaki N, Takahashi M, et al. Cancer-associated fibroblasts that restrain cancer progression: hypotheses and perspectives[J]. Cancer Sci, 2020, 111(4): 1047-1057. DOI: 10.1111/cas.14346.
[13]	Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts[J]. Nat Rev Clin Oncol, 2021, 18(12): 792-804. DOI: 10.1038/s41571-021-00546-5. pmid: 34489603
[14]	Mucciolo G, Araos Henríquez J, Jihad M, et al. EGFR-activated myofibroblasts promote metastasis of pancreatic cancer[J]. Cancer Cell, 2024, 42(1): 101-118.e11. DOI: 10.1016/j.ccell.2023.12.002. pmid: 38157863
[15]	Mori Y, Okimoto Y, Sakai H, et al. Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer[J]. Cell Rep Med, 2024, 5(5): 101532. DOI: 10.1016/j.xcrm.2024.101532.
[16]	Foster DS, Januszyk M, Delitto D, et al. Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin[J]. Cancer Cell, 2022, 40(11): 1392-1406.e7. DOI: 10.1016/j.ccell.2022.09.015. pmid: 36270275
[17]	Öhlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer[J]. J Exp Med, 2017, 214(3): 579-596. DOI: 10.1084/jem.20162024.
[18]	Schwörer S, Cimino FV, Ros M, et al. Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines[J]. Cancer Res, 2023, 83(10): 1596-1610. DOI: 10.1158/0008-5472.Can-22-2316. pmid: 36912618
[19]	Ma C, Yang C, Peng A, et al. Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment[J]. Mol Cancer, 2023, 22(1): 170. DOI: 10.1186/s12943-023-01876-x. pmid: 37833788
[20]	Bartoschek M, Oskolkov N, Bocci M, et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing[J]. Nat Commun, 2018, 9(1): 5150. DOI: 10.1038/s41467-018-07582-3. pmid: 30514914
[21]	Liu C, Zhang M, Yan X, et al. Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression[J]. Sci Adv, 2023, 9(4): eadd8977. DOI: 10.1126/sciadv.add8977.
[22]	Li X, Sun Z, Peng G, et al. Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer[J]. Theranostics, 2022, 12(2): 620-638. DOI: 10.7150/thno.60540. pmid: 34976204
[23]	Zhang H, Yue X, Chen Z, et al. Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials[J]. Mol Cancer, 2023, 22(1): 159. DOI: 10.1186/s12943-023-01860-5. pmid: 37784082
[24]	Zhu GQ, Tang Z, Huang R, et al. CD36⁺ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor[J]. Cell Discov, 2023, 9(1): 25. DOI: 10.1038/s41421-023-00529-z.
[25]	Dominguez CX, Müller S, Keerthivasan S, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15⁺ myofibroblasts as a determinant of patient response to cancer immunotherapy[J]. Cancer Discov, 2020, 10(2): 232-253. DOI: 10.1158/2159-8290.Cd-19-0644. pmid: 31699795
[26]	Song J, Wei R, Liu C, et al. Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response[J]. Nat Commun, 2025, 16(1): 2175. DOI: 10.1038/s41467-025-57465-7.
[27]	Chen X, Zhou Z, Xie L, et al. Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches[J]. Cancer Cell, 2025, 43(12): 2224-2240.e9. DOI: 10.1016/j.ccell.2025.09.001.
[28]	Wang Y, Liang Y, Xu H, et al. Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response[J]. Cell Discov, 2021, 7(1): 36. DOI: 10.1038/s41421-021-00271-4. pmid: 34035226
[29]	Sebastian A, Hum NR, Martin KA, et al. Single-cell transcriptomic analysis of tumor-derived fibroblasts and normal tissue-resident fibroblasts reveals fibroblast heterogeneity in breast cancer[J]. Cancers (Basel), 2020, 12(5): 1307. DOI: 10.3390/cancers12051307.
[30]	Ou Z, Lin S, Qiu J, et al. Single-nucleus RNA sequencing and spatial transcriptomics reveal the immunological microenvironment of cervical squamous cell carcinoma[J]. Adv Sci (Weinh), 2022, 9(29): e35986392. DOI: 10.1002/advs.202203040.
[31]	Grauel AL, Nguyen B, Ruddy D, et al. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts[J]. Nat Commun, 2020, 11(1): 6315. DOI: 10.1038/s41467-020-19920-5. pmid: 33298926
[32]	Davidson G, Helleux A, Vano YA, et al. Mesenchymal-like tumor cells and myofibroblastic cancer-associated fibroblasts are associated with progression and immunotherapy response of clear cell renal cell carcinoma[J]. Cancer Res, 2023, 83(17): 2952-2969. DOI: 10.1158/0008-5472.Can-22-3034.
[33]	Affo S, Nair A, Brundu F, et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations[J]. Cancer Cell, 2021, 39(6): 866-882.e11. DOI: 10.1016/j.ccell.2021.03.012. pmid: 33930309
[34]	Mellone M, Piotrowska K, Venturi G, et al. ATM regulates differentiation of myofibroblastic cancer-associated fibroblasts and can be targeted to overcome immunotherapy resistance[J]. Cancer Res, 2022, 82(24): 4571-4585. DOI: 10.1158/0008-5472.Can-22-0435. pmid: 36353752
[35]	Piffkó A, Yang K, Panda A, et al. Radiation-induced amphiregulin drives tumour metastasis[J]. Nature, 2025, 643(8072): 810-819. DOI: 10.1038/s41586-025-08994-0.
[36]	Zhou J, Xu Y, Li Y, et al. Cancer-associated fibroblasts derived amphiregulin promotes HNSCC progression and drug resistance of EGFR inhibitor[J]. Cancer Lett, 2025, 622: 217710. DOI: 10.1016/j.canlet.2025.217710.
[37]	Kieffer Y, Hocine HR, Gentric G, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer[J]. Cancer Discov, 2020, 10(9): 1330-1351. DOI: 10.1158/2159-8290.Cd-19-1384. pmid: 32434947
[38]	Fang H, Dai W, Gu R, et al. myCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment[J]. J Hematol Oncol, 2024, 17(1): 126. DOI: 10.1186/s13045-024-01643-5.
[39]	Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer[J]. Cancer Cell, 2018, 33(3): 463-479.e10. DOI: 10.1016/j.ccell.2018.01.011. pmid: 29455927
[40]	Cogliati B, Yashaswini CN, Wang S, et al. Friend or foe? The elusive role of hepatic stellate cells in liver cancer[J]. Nat Rev Gastroenterol Hepatol, 2023, 20(10): 647-661. DOI: 10.1038/s41575-023-00821-z. pmid: 37550577
[41]	Huang H, Wang Z, Zhang Y, et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer[J]. Cancer Cell, 2022, 40(6): 656-673.e7. DOI: 10.1016/j.ccell.2022.04.011.
[42]	Kerdidani D, Aerakis E, Verrou KM, et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts[J]. J Exp Med, 2022, 219(2): e20210815. DOI: 10.1084/jem.20210815.
[43]	Yamamoto Y, Kasashima H, Fukui Y, et al. The heterogeneity of cancer-associated fibroblast subpopulations: their origins, biomarkers, and roles in the tumor microenvironment[J]. Cancer Sci, 2023, 114(1): 16-24. DOI: 10.1111/cas.15609.
[44]	Cheng PS, Zaccaria M, Biffi G. Functional heterogeneity of fibroblasts in primary tumors and metastases[J]. Trends Cancer, 2025, 11(2): 135-153. DOI: 10.1016/j.trecan.2024.11.005. pmid: 39674792
[45]	Jenkins BH, Tracy I, Rodrigues MFSD, 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[J]. Mol Cancer, 2025, 24(1): 3. DOI: 10.1186/s12943-024-02191-9. pmid: 39757146
[46]	Liu L, Ba Y, Yang S, et al. FOS-driven inflammatory CAFs promote colorectal cancer liver metastasis via the SFRP1-FGFR2-HIF1 axis[J]. Theranostics, 2025, 15(10): 4593-4613. DOI: 10.7150/thno.111625. pmid: 40225580
[47]	Yu X, Qian J, Ding L, et al. Galectin-1: a traditionally immunosuppressive protein displays context-dependent capacities[J]. Int J Mol Sci, 2023, 24(7): 37047471. DOI: 10.3390/ijms24076501.
[48]	Chen J, Guo W, Du P, et al. MIF inhibition alleviates vitiligo progression by suppressing CD8⁺ T cell activation and proliferation[J]. J Pathol, 2023, 260(1): 84-96. DOI: 10.1002/path.6073.
[49]	Xiang X, Niu YR, Wang ZH, et al. Cancer-associated fibroblasts: vital suppressors of the immune response in the tumor microenvironment[J]. Cytokine Growth Factor Rev, 2022, 67: 35-48. DOI: 10.1016/j.cytogfr.2022.07.006.
[50]	Kerneur C, Cano CE, Olive D. Major pathways involved in macrophage polarization in cancer[J]. Front Immunol, 2022, 13: 1026954. DOI: 10.3389/fimmu.2022.1026954.
[51]	Arpinati L, Scherz-Shouval R. From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts[J]. Trends Cancer, 2023, 9(5): 421-443. DOI: 10.1016/j.trecan.2023.01.007. pmid: 36870916
[52]	Nicolas AM, Pesic M, Engel E, et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer[J]. Cancer Cell, 2022, 40(2): 168-184.e13. DOI: 10.1016/j.ccell.2022.01.004. pmid: 35120600
[53]	Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming[J]. Theranostics, 2021, 11(17): 8322-8336. DOI: 10.7150/thno.62378. pmid: 34373744
[54]	McAndrews KM, Chen Y, Darpolor JK, et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-mediated therapy resistance in pancreatic cancer[J]. Cancer Discov, 2022, 12(6): 1580-1597. DOI: 10.1158/2159-8290.Cd-20-1484. pmid: 35348629
[55]	Kennel KB, Bozlar M, De Valk AF, et al. Cancer-associated fibroblasts in inflammation and antitumor immunity[J]. Clin Cancer Res, 2023, 29(6): 1009-1016. DOI: 10.1158/1078-0432.Ccr-22-1031.
[56]	Zhang Y, Ling L, Murad R, et al. Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer[J]. Cancer Cell, 2025, 43(9): 1677-1696.e15. DOI: 10.1016/j.ccell.2025.06.021.