Immunoregulation mechanism and clinical significance of cancer-associated fibroblasts in ovarian cancer

doi:10.3760/cma.j.cn371439-20251128-00061

Abstract

Abstract:

The tumor microenvironment plays a critical role in the occurrence，progression，and therapeutic resistance of ovarian cancer. Among the tumor stroma，cancer-associated fibroblasts（CAFs）are the most abundant cell types and participate in immune regulation and promote tumor immune evasion through multiple mechanisms. CAFs modulate immune cell functions by secreting cytokines such as IL-6，TGF-β，and CXCL12，and influence immune cell infiltration and spatial distribution via extracellular matrix remodeling. Clinically，the unique role of CAFs can be exerted by selectively eliminating CAFs or targeting CAF-mediated signaling pathways to weaken their support for tumor progression. CAF-related biomarkers are closely associated with patient prognosis and hold significant value in guiding clinical treatment selection and prognostic assessment. A deeper understanding of the immune regulation mechanisms of CAFs is of critical clinical significance for overcoming immunotherapy resistance and improving therapeutic outcomes in ovarian cancer.

Key words: Ovarian neoplasms, Cancer-associated fibroblasts, Immunomodulation, Tumor microenvironment

Sun Xiaoning, He Pan, Wang Xian, Yao Shujuan. Immunoregulation mechanism and clinical significance of cancer-associated fibroblasts in ovarian cancer[J]. Journal of International Oncology, 2026, 53(6): 376-380.

References 53

[1]	Deng YQ, Tan Y, Zhou DM, et al. Single-cell RNA-sequencing atlas reveals the tumor microenvironment of metastatic high-grade serous ovarian carcinoma[J]. Front Immunol, 2022, 13: 923194. DOI: 10.3389/fimmu.2022.923194.
[2]	郭晓娟, 杜瑞娟, 陈丽平, 等. WW结构域E3泛素连接酶1调控卵巢癌肿瘤微环境中的免疫浸润[J]. 南方医科大学学报, 2025, 45(5): 1063-1073. DOI: 10.12122/j.issn.1673-4254.2025.05.20.
[3]	Lheureux S, Gourley C, Vergote I, et al. Epithelial ovarian cancer[J]. Lancet, 2019, 393(10177): 1240-1253. DOI: 10.1016/s0140-6736(18)32552-2. pmid: 30910306
[4]	Xu YC, Sun DT, He JQ, et al. Cancer-associated fibroblasts in ovarian cancer: research progress[J]. Front Oncol, 2025, 15: 1504762. DOI: 10.3389/fonc.2025.1504762.
[5]	Luo JL, Xiang XH, Gong GY, et al. Cancer-associated fibroblast-mediated immune evasion: molecular mechanisms of stromal-immune crosstalk in the tumor microenvironment[J]. Front Immunol, 2025, 16: 1617662. DOI: 10.3389/fimmu.2025.1617662.
[6]	Hu Y, Recouvreux MS, Haro M, et al. INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer[J]. NPJ Precis Oncol, 2024, 8(1): 35. DOI: 10.1038/s41698-024-00523-y. pmid: 38360876
[7]	Xu TY, Liu ZH, Huang LW, et al. Modulating the tumor immune microenvironment with nanoparticles: a sword for improving the efficiency of ovarian cancer immunotherapy[J]. Front Immunol, 2022, 13: 1057850. DOI: 10.3389/fimmu.2022.1057850.
[8]	Ding B, Ye Z, Yin H, et al. Comprehensive single-cell analysis reveals heterogeneity of fibroblast subpopulations in ovarian cancer tissue microenvironment[J]. Heliyon, 2024, 10(6): e27873. DOI: 10.1016/j.heliyon.2024.e27873.
[9]	Wang J, Cheng FHC, Tedrow J, et al. Modulation of immune infiltration of ovarian cancer tumor microenvironment by specific subpopulations of fibroblasts[J]. Cancers (Basel), 2020, 12(11): 3184. DOI: 10.3390/cancers12113184.
[10]	Tang HJ, Chu YJ, Huang ZJ, et al. The metastatic phenotype shift toward myofibroblast of adipose-derived mesenchymal stem cells promotes ovarian cancer progression[J]. Carcinogenesis, 2020, 41(2): 182-193. DOI: 10.1093/carcin/bgz083. pmid: 31046126
[11]	张丹, 宋克娟, 任远中, 等. 卵巢癌细胞来源的外泌体对成纤维细胞分化的影响[J]. 中华肿瘤杂志, 2022, 44(7): 737-742. DOI: 10.3760/cma.j.cn112152-20200110-00021.
[12]	Buddenkotte T, Rundo L, Woitek R, et al. Deep learning-based segmentation of multisite disease in ovarian cancer[J]. Eur Radiol Exp, 2023, 7(1): 77. DOI: 10.1186/s41747-023-00388-z. pmid: 38057616
[13]	Xiao J, Yang ZY, Wang SY, et al. CD248-expressing cancer-associated fibroblasts induce epithelial-mesenchymal transition of non-small cell lung cancer via inducing M2-polarized macrophages[J]. Sci Rep, 2024, 14(1): 14343. DOI: 10.1038/s41598-024-65435-0. pmid: 38906929
[14]	Chen PY, Wei WF, Wu HZ, et al. Cancer-associated fibroblast heterogeneity: a factor that cannot be ignored in immune microenvironment remodeling[J]. Front Immunol, 2021, 12: 671595. DOI: 10.3389/fimmu.2021.671595.
[15]	Geng XL, Chen HZ, Zhao L, et al. Cancer-associated fibroblast (CAF) heterogeneity and targeting therapy of CAFs in pancreatic cancer[J]. Front Cell Dev Biol, 2021, 9: 655152. DOI: 10.3389/fcell.2021.655152.
[16]	Guo TC, Xu JF. Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy[J]. Cancer Metastasis Rev, 2024, 43(3): 1095-1116. DOI: 10.1007/s10555-024-10186-7.
[17]	Xu JF, Fang YF, Chen KL, et al. Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer[J]. Clin Cancer Res, 2022, 28(16): 3590-3602. DOI: 10.1158/1078-0432.Ccr-22-0296. pmid: 35675036
[18]	Xia ZH, De Wever O. The plasticity of cancer-associated fibroblasts[J]. Trends Cancer, 2025, 11(8): 770-789. DOI: 10.1016/j.trecan.2025.04.012. pmid: 40473532
[19]	李高鹏, 何佳, 王青青. 肿瘤相关成纤维细胞对肿瘤免疫调控作用的研究进展[J]. 浙江大学学报(医学版), 2018, 47(5): 558-563. DOI: 10.3785/j.issn.1008-9292.2018.10.17.
[20]	Pawar JS, Salam MA, Dipto MSU, et al. Cancer-associated fibroblasts: immunosuppressive crosstalk with tumor-infiltrating immune cells and implications for therapeutic resistance[J]. Cancers (Basel), 2025, 17(15): 2484. DOI: 10.3390/cancers17152484.
[21]	Liu HS, Xu CN, Wang P, et al. CRCs-CAFs crosstalk-targeted nano-delivery system reprograms tumor microenvironment for oxaliplatin resistance reversing and liver metastasis inhibition in colorectal cancer[J]. Bioact Mater, 2025, 54: 126-143. DOI: 10.1016/j.bioactmat.2025.08.002. pmid: 40837498
[22]	Ning X, Wang Y, Zhai LN, et al. PGRN mediates the crosstalk between ovarian cancer cells and CAFs and reshapes tumor immune microenvironment[J]. Int Immunopharmacol, 2025, 164: 115362. DOI: 10.1016/j.intimp.2025.115362.
[23]	Xiao YT, Jiang YY, Bao T, et al. CAF-driven mechanotransduction via collagen remodeling accelerates tumor cell cycle progression[J]. Gels, 2025, 11(8): 642. DOI: 10.3390/gels11080642.
[24]	Xu JB, Yao H, Wang JF, et al. Perineural invasion and the "cold" tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities[J]. Front Immunol, 2025, 16: 1650117. DOI: 10.3389/fimmu.2025.1650117.
[25]	Zhang C, Song YS, Cui XB, et al. Regulatory T cells and matrix-producing cancer associated fibroblasts contribute on the immune resistance and progression of prognosis related tumor subtypes in ccRCC[J]. Sci Rep, 2025, 15(1): 20533. DOI: 10.1038/s41598-025-06051-4.
[26]	Zeng Y, Li BH, Liang YY, et al. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment[J]. Faseb J, 2019, 33(5): 6596-6608. DOI: 10.1096/fj.201802067RR. pmid: 30802149
[27]	Zhang K, Liu KY, Hu BX, et al. Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer[J]. Nat Commun, 2024, 15(1): 9050. DOI: 10.1038/s41467-024-53233-1. pmid: 39426954
[28]	Pan BY, Wan T, Zhou Y, et al. The MYBL2-CCL2 axis promotes tumor progression and resistance to anti-PD-1 therapy in ovarian cancer by inducing immunosuppressive macrophages[J]. Cancer Cell Int, 2023, 23(1): 248. DOI: 10.1186/s12935-023-03079-2. pmid: 37865750
[29]	Deng SH, Cheng DL, Wang J, et al. MYL9 expressed in cancer-associated fibroblasts regulate the immune microenvironment of colorectal cancer and promotes tumor progression in an autocrine manner[J]. J Exp Clin Cancer Res, 2023, 42(1): 294. DOI: 10.1186/s13046-023-02863-2. pmid: 37926835
[30]	Liang QJ, Xu ZJ, Liu YH, et al. NR2F1 regulates TGF-β1-mediated epithelial-mesenchymal transition affecting platinum sensitivity and immune response in ovarian cancer[J]. Cancers (Basel), 2022, 14(19): 4639. DOI: 10.3390/cancers14194639.
[31]	Wang W, Liu XN, Xu SJ, et al. CD38 contributes to tumor progression and tumor microenvironment reshaping in epithelial ovarian cancer[J]. Transl Oncol, 2025, 57: 102414. DOI: 10.1016/j.tranon.2025.102414.
[32]	Wang YX, Ding WH, Hao WJ, et al. CXCL3/TGF-β-mediated crosstalk between CAFs and tumor cells augments RCC progression and sunitinib resistance[J]. iScience, 2024, 27(7): 110224. DOI: 10.1016/j.isci.2024.110224.
[33]	Mentucci FM, Ferrara MG, Ercole A, et al. Interplay between cancer-associated fibroblasts and dendritic cells: implications for tumor immunity[J]. Front Immunol, 2025, 16: 1515390. DOI: 10.3389/fimmu.2025.1515390.
[34]	Ahuja S, Sureka N, Zaheer S. Unraveling the intricacies of cancer-associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk[J]. APMIS, 2024, 132(12): 906-927. DOI: 10.1111/apm.13447. pmid: 38873945
[35]	Chen PP, Geng HY, Ma BZ, et al. Integrating spatial omics and single-cell mass spectrometry imaging reveals tumor-host metabolic interplay in hepatocellular carcinoma[J]. Proc Natl Acad Sci U S A, 2025, 122(31): e2505789122. DOI: 10.1073/pnas.2505789122.
[36]	Zhu YF, Li XY, Wang L, et al. Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment[J]. Front Endocrinol (Lausanne), 2022, 13: 988295. DOI: 10.3389/fendo.2022.988295.
[37]	Kay EJ, Zanivan S. The tumor microenvironment is an ecosystem sustained by metabolic interactions[J]. Cell Rep, 2025, 44(3): 115432. DOI: 10.1016/j.celrep.2025.115432.
[38]	Zhang DD, Li JK, Xu XY, et al. CAF-derived GLUT1 and its role in modulating ovarian cancer progression: a multi-dimensional analysis of the tumor microenvironment[J]. Commun Biol, 2025, 8(1): 1020. DOI: 10.1038/s42003-025-08380-6.
[39]	Shen J, Wu RP, Yin T, et al. Harnessing the power of cancer-associated fibroblasts to revolutionize pancreatic cancer treatment[J]. Cancer Biol Med, 2025, 22(12): 1473-1492. DOI: 10.20892/j.issn.2095-3941.2025.0288.
[40]	Lan YF, Xu H, Jin LY. HJURP derived from cancer-associated fibroblasts promotes glutamine metabolism to induce resistance to doxorubicin in ovarian cancer[J]. Tohoku J Exp Med, 2024, 264(1): 31-39. DOI: 10.1620/tjem.2024.J041. pmid: 38866531
[41]	Ding B, Ye Z, Yin H, et al. Exosomes derived from ovarian cancer cells regulate proliferation and migration of cancer-associated fibroblasts[J]. Genomics, 2023, 115(5): 110703. DOI: 10.1016/j.ygeno.2023.110703.
[42]	Dai JM, Sun K, Li C, et al. Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1α[J]. Clin Transl Oncol, 2023, 25(6): 1606-1616. DOI: 10.1007/s12094-022-03054-9.
[43]	Sun LY, Ke ML, Yin MY, et al. Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways[J]. Cancer Sci, 2024, 115(1): 155-169. DOI: 10.1111/cas.16014.
[44]	Sun LY, Ke ML, Wang XY, et al. FAP^high α-SMA^low cancer-associated fibroblast-derived SLPI protein encapsulated in extracellular vesicles promotes ovarian cancer development via activation of PI3K/AKT and downstream signaling pathways[J]. Mol Carcinog, 2022, 61(10): 910-923. DOI: 10.1002/mc.23445.
[45]	Zheng SQ, Liang JY, Tang YH, et al. Dissecting the role of cancer-associated fibroblast-derived biglycan as a potential therapeutic target in immunotherapy resistance: a tumor bulk and single-cell transcriptomic study[J]. Clin Transl Med, 2023, 13(2): e1189. DOI: 10.1002/ctm2.1189. pmid: 36772945
[46]	Ford K, Hanley CJ, Mellone M, et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors[J]. Cancer Res, 2020, 80(9): 1846-1860. DOI: 10.1158/0008-5472.Can-19-3158. pmid: 32122909
[47]	Hanley CJ, Thomas GJ. T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting[J]. Br J Cancer, 2020, 123(9): 1353-1355. DOI: 10.1038/s41416-020-1020-6.
[48]	Lunina NA, Safina DR, Kostrov SV. Cancer-associated fibroblasts: heterogeneity and bimodality in oncogenesis[J]. Mol Biol (Mosk), 2023, 57(5): 739-770. DOI: 10.1134/S0026893323050096. pmid: 37752641
[49]	Wu ZH, Luo ML, Hu HY, et al. Hidden forces: the impact of cancer-associated fibroblasts on non-small cell lung cancer development and therapy[J]. J Transl Med, 2025, 23(1): 830. DOI: 10.1186/s12967-025-06791-x. pmid: 40713753
[50]	Carvalho RF, do Canto LM, Abildgaard C, et al. Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer[J]. Cell Commun Signal, 2022, 20(1): 176. DOI: 10.1186/s12964-022-00991-4. pmid: 36352420
[51]	Wang H, Liang Y, Liu Z, et al. POSTN⁺ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma[J]. J Immunother Cancer, 2024, 12(7): e008721. DOI: 10.1136/jitc-2023-008721.
[52]	Maia A, Schöllhorn A, Schuhmacher J, et al. CAF-immune cell crosstalk and its impact in immunotherapy[J]. Semin Immunopathol, 2023, 45(2): 203-214. DOI: 10.1007/s00281-022-00977-x.
[53]	Pei LP, Liu Y, Liu L, et al. Roles of cancer-associated fibroblasts (CAFs) in anti-PD-1/PD-L1 immunotherapy for solid cancers[J]. Mol Cancer, 2023, 22(1): 29. DOI: 10.1186/s12943-023-01731-z.