Research progress of cancer-associated fibroblasts in colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

MA Mingli ¹ , WANG Xu ¹ , XU Jianjiang ¹ , CHEN Yan ¹ , Wang Xiangwen ² ,  JIANG Lei ²

1. The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding author：

JIANG Lei, Email: jiangyjsggyx@163.com

Keywords：

cancer-associated fibroblast; colorectal cancer; tumor imicroenvironment; therapeutic strategy

DOI：

10.7507/1007-9424.202504152

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To explore the key roles of cancer-associated fibroblasts (CAFs) in the pathogenesis, development, therapeutic resistance, and immune microenvironment modulation of colorectal cancer (CRC). Methods Through a systematic review of existing literature, this article summarizes the origin and heterogeneity of CAFs, their mechanisms of action in CRC occurrence and progression, and reviews potential CAF-targeting therapeutic strategies. Results CAFs are highly heterogeneous cell populations that drive CRC progression by promoting tumor proliferation, invasion, metastasis, angiogenesis, and inducing therapy resistance. Targeting specific CAF subsets or their key signaling pathways has demonstrated significant tumor-suppressive effects in preclinical studies. Conclusions As a crucial component of the tumor microenvironment, CAFs play important roles in the development and therapeutic resistance of CRC. Theoretically, CAF-targeting strategies hold great potential for optimizing CRC treatment. However, translating the therapeutic potential of CAFs into clinical practice still faces numerous challenges, primarily due to limited understanding of their origins, functions, and mechanisms of action. Future research needs to further decipher the subtype-specific functions of CAFs to advance the development of precise treatment strategies.

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2.	Franzè E, Di Grazia A, Sica GS, et al. Interleukin-34 enhances the tumor promoting function of colorectal cancer-associated fibroblasts. Cancers (Basel), 2020, 12(12): 3537. doi: 10.3390/cancers12123537.
3.	Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res, 2020, 39(1): 112. doi: 10.1186/s13046-020-01611-0.
4.	Kobayashi H, Gieniec KA, Lannagan TRM, et al. The origin and contribution of cancer-associated fibroblasts in colorectal carcinogenesis. Gastroenterology, 2022, 162(3): 890-906.
5.	Guillén Díaz-Maroto N, Sanz-Pamplona R, Berdiel-Acer M, et al. Noncanonical TGFβ pathway relieves the blockade of IL1β/TGFβ-mediated crosstalk between tumor and stroma: TGFBR1 and TAK1 inhibition in colorectal cancer. Clin Cancer Res, 2019, 25(14): 4466-4479.
6.	Li Z, Zhang J, Zhou J, et al. Correction: Li et al. Nodal facilitates differentiation of fibroblasts to cancer-associated fibroblasts that support tumor growth in melanoma and colorectal cancer. Cells, 2019, 8: 538. doi: 10.3390/cells8060538.
7.	Ciszewski WM, Wawro ME, Sacewicz-Hofman I, et al. Cytoskeleton reorganization in EndMT-the role in cancer and fibrotic diseases. Int J Mol Sci, 2021, 22(21): 11607. doi: 10.3390/ijms222111607.
8.	Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview. Pharmacol Res, 2021, 170: 105739. doi: 10.1016/j.phrs.2021.105739.
9.	Pellinen T, Paavolainen L, Martín-Bernabé A, et al. Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features. J Natl Cancer Inst, 2023, 115(1): 71-82.
10.	Jing SY, Liu D, Feng N, et al. Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma. Genome Med, 2024, 16(1): 98.
11.	Yang S, Zhang D, Sun Q, et al. Single-cell and spatial transcriptome profiling identifies the transcription factor BHLHE40 as a driver of EMT in metastatic colorectal cancer. Cancer Res, 2024, 84(13): 2202-2217.
12.	Zhang K, Liu K, Hu B, et al. Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer. Nat Commun, 2024, 15(1): 9050. doi: 10.1038/s41467-024-53233-1.
13.	Liu Y, Chen H, Yan X, et al. MyD88 in myofibroblasts enhances nonalcoholic fatty liver disease-related hepatocarcinogenesis via promoting macrophage M2 polarization. Cell Commun Signal, 2024, 22(1): 86. doi: 10.1186/s12964-024-01489-x.
14.	Ma H, Wang J, Zhao X, et al. Periostin promotes colorectal tumorigenesis through integrin-FAK-Src pathway-mediated YAP/TAZ activation. Cell Rep, 2020, 30(3): 793-806.
15.	Heichler C, Schmied A, Enderle K, et al. Targeting STAT3 signaling in COL1+ fibroblasts controls colitis-associated cancer in mice. Cancers (Basel), 2022, 14(6): 1472. doi: 10.3390/cancers14061472.
16.	Kobayashi H, Gieniec KA, Wright JA, et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology, 2021, 160(4): 1224-1239.
17.	Denton AE, Roberts EW, Fearon DT. Stromal cells in the tumor microenvironment. Adv Exp Med Biol, 2018, 1060: 99-114.
18.	Sarkar M, Nguyen T, Gundre E, et al. Cancer-associated fibroblasts: the chief architect in the tumor microenvironment. Front Cell Dev Biol, 2023 Jan 30: 11: 1089068. doi: 10.3389/fcell.2023.1089068.
19.	van Genderen MNG, Kneppers J, Zaalberg A, et al. Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties. NPJ Syst Biol Appl, 2024, 10(1): 20. doi: 10.1038/s41540-024-00344-6.
20.	Yang X, Zheng H, Huang J, et al. Co-inhibition of PGF and VEGFA enhances the effectiveness of immunotherapy in bladder cancer. Int J Med Sci, 2024, 21(15): 2870-2882.
21.	Shen Y, Wang X, Lu J, et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell, 2020, 37(6): 800-817.
22.	Piwocka O, Piotrowski I, Suchorska WM, et al. Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy. Front Mol Biosci, 2024, 11: 1343523. doi: 10.3389/fmolb.2024.1343523.
23.	Lunina NA. , Safina DR, Kostrov SV. Cancer-associated fibroblasts: heterogeneity and bimodality in oncogenesis. Mol Biol (Mosk) 2023, 57 (5), 739-770.
24.	Peña C, Céspedes MV, Lindh MB, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res, 2013, 73(4): 1287-1297.
25.	Xie Q, Liu X, Liu R, et al. Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer. Mol Cancer, 2024, 23(1): 252. doi: 10.1186/s12943-024-02166-w.
26.	Wanandi SI, Hilbertina N, Siregar NC, et al. Cancer-associated fibroblast (CAF) secretomes-induced epithelial-mesenchymal transition on HT-29 colorectal carcinoma cells associated with hepatocyte growth factor (HGF) signalling. J Pak Med Assoc 2021, 71(Suppl 2) (2), S18-s24.
27.	Liao J, Chen R, Lin B, et al. Cross-talk between the TGF-β and cell adhesion signaling pathways in cancer. Int J Med Sci, 2024, 21(7): 1307-1320.
28.	Bauer J, Emon MAB, Staudacher JJ, et al. Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling. Sci Rep, 2020, 10(1): 50. doi: 10.1038/s41598-019-55687-6.
29.	Sun S, Zhang Y, Li Y, et al. Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs. Front Immunol, 2023, 14: 1161628. doi: 10.3389/fimmu.2023.1161628.
30.	Tommelein J, De Vlieghere E, Verset L, et al. Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF1R activation. Cancer Res, 2018, 78(3): 659-670.
31.	Peng S, Chen D, Cai J, et al. Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis. Mol Oncol, 2021, 15(5): 1391-1411.
32.	Sung PJ, Rama N, Imbach J, et al. Cancer-associated fibroblasts produce Netrin-1 to control cancer cell plasticity. Cancer Res, 2019, 79(14): 3651-3661.
33.	Zhao Z, Zhu Y. FAP, CD10, and GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer. BMC Cancer, 2023, 23(1): 507. doi: 10.1186/s12885-023-11011-0.
34.	Garvey CM, Lau R, Sanchez A, et al. Anti-EGFR therapy induces EGF secretion by cancer-associated fibroblasts to confer colorectal cancer chemoresistance. Cancers (Basel), 2020, 12(6): 1393. doi: 10.3390/cancers12061393.
35.	Chen X, Liu Y, Zhang Q, et al. Exosomal miR-590-3p derived from cancer-associated fibroblasts confers radioresistance in colorectal cancer. Mol Ther Nucleic Acids, 2020, 24: 113-126.
36.	André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med, 2020, 383(23): 2207-2218.
37.	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. Mol Cancer, 2023, 22(1): 159. doi: 10.1186/s12943-023-01860-5.
38.	Arab S, Hasannejad F. An overview of current therapeutic strategies for glioblastoma and the role of CD73 as an alternative curative approach. Clin Transl Oncol, 2022, 24(5): 742-756.
39.	Zadka Ł, Chabowski M, Grybowski D, et al. Interplay of stromal tumor-infiltrating lymphocytes, normal colonic mucosa, cancer-associated fibroblasts, clinicopathological data and the immunoregulatory molecules of patients diagnosed with colorectal cancer. Cancer Immunol Immunother, 2021, 70(9): 2681-2700.
40.	Bigos KJ, Quiles CG, Lunj S, et al. Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours. Front Oncol, 2024, 14: 1331355. doi: 10.3389/fonc.2024.1331355.
41.	Li Z, Zhou J, Zhang J, et al. Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5. Int J Cancer, 2019, 145(7): 1946-1957.
42.	Sun D, Tan L, Chen Y, et al. CXCL5 impedes CD8⁺ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis. J Exp Clin Cancer Res, 2024, 43(1): 202. doi: 10.1186/s13046-024-03122-8.
43.	Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol, 2021, 18(12): 792-804.
44.	Huang L, Lu W, Wu R, et al. Interferon-driven CAF reprogramming augments immunogenic response to neoadjuvant radiotherapy in colorectal cancer. Cell Rep Med, 2025, 6(8): 102251. doi: 10.1016/j.xcrm.2025.102251.
45.	Wang H, Lin B, Wang Z, et al. Fusobacterium nucleatum increases CTGF expression through TLR2-YAP signaling axis in cancer-associated fibroblasts, thereby promoting colorectal cancer progression. Cancer Cell Int, 2025, 25(1): 381. doi: 10.1186/s12935-025-04023-2.
46.	Chen L, Qiu X, Wang X, et al. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression. Biochem Biophys Res Commun, 2017, 487(1): 8-14.
47.	Yuan Q, Gu J, Zhang J, et al. MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization. Cell Rep, 2021, 34(5): 108724. doi: 10.1016/j.celrep.2021.108724.
48.	Xie L, Jiang FC, Zhang LM, et al. Targeting of MyD88 homodimerization by novel synthetic inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer. J Natl Cancer Inst, 2015, 108(4): djv364. doi: 10.1093/jnci/djv364.
49.	Heichler C, Scheibe K, Schmied A, et al. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut, 2020, 69(7): 1269-1282.
50.	Chalikonda G, Lee H, Sheik A, et al. Targeting key transcriptional factor STAT3 in colorectal cancer. Mol Cell Biochem, 2021, 476(9): 3219-3228.
51.	Chen CY, Yang SH, Chang PY, et al. Cancer-associated-fibroblast-mediated paracrine and autocrine SDF-1/CXCR4 signaling promotes stemness and aggressiveness of colorectal cancers. Cells, 2024, 13(16): 1334. doi: 10.3390/cells13161334.
52.	Kang S, Tanaka T, Narazaki M, et al. Targeting interleukin-6 signaling in clinic. Immunity, 2019, 50(4): 1007-1023.
53.	Ghatak S, Hascall VC, Karamanos N, et al. Interplay between chemotherapy-activated cancer associated fibroblasts and cancer initiating cells expressing CD44v6 promotes colon cancer resistance. Front Oncol, 2022, 12: 906415. doi: 10.3389/fonc.2022.906415.
54.	Chen K, Kolls JK. Interluekin-17A (IL17A). Gene, 2017, 614: 8-14.
55.	Liu Y, Paauwe M, Nixon AB, et al. Endoglin targeting: lessons learned and questions that remain. Int J Mol Sci, 2020, 22(1): 147. doi: 10.3390/ijms22010147.
56.	Huang TX, Tan XY, Huang HS, et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut, 2022, 71(2): 333-344.
57.	Jacobs J, Deschoolmeester V, Zwaenepoel K, et al. CD70: an emerging target in cancer immunotherapy. Pharmacol Ther, 2015, 155: 1-10.
58.	Diep CH, Spartz A, Truong TH, et al. Progesterone receptor signaling promotes cancer associated fibroblast mediated tumorigenicity in ER+ breast cancer. Endocrinology, 2024, 165(9): bqae092. doi: 10.1210/endocr/bqae092.
59.	Kono M, Komatsuda H, Yamaki H, et al. Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma. Oncoimmunology, 2022, 11(1): 2021619. doi: 10.1080/2162402X.2021.2021619.

1. Oleynikova NA, Danilova NV, Mikhailov IA, et al. Cancer-associated fibroblasts and their significance in tumor progression. Arkh Patol, 2020, 82(1): 68-77.
2. Franzè E, Di Grazia A, Sica GS, et al. Interleukin-34 enhances the tumor promoting function of colorectal cancer-associated fibroblasts. Cancers (Basel), 2020, 12(12): 3537. doi: 10.3390/cancers12123537.
3. Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res, 2020, 39(1): 112. doi: 10.1186/s13046-020-01611-0.
4. Kobayashi H, Gieniec KA, Lannagan TRM, et al. The origin and contribution of cancer-associated fibroblasts in colorectal carcinogenesis. Gastroenterology, 2022, 162(3): 890-906.
5. Guillén Díaz-Maroto N, Sanz-Pamplona R, Berdiel-Acer M, et al. Noncanonical TGFβ pathway relieves the blockade of IL1β/TGFβ-mediated crosstalk between tumor and stroma: TGFBR1 and TAK1 inhibition in colorectal cancer. Clin Cancer Res, 2019, 25(14): 4466-4479.
6. Li Z, Zhang J, Zhou J, et al. Correction: Li et al. Nodal facilitates differentiation of fibroblasts to cancer-associated fibroblasts that support tumor growth in melanoma and colorectal cancer. Cells, 2019, 8: 538. doi: 10.3390/cells8060538.
7. Ciszewski WM, Wawro ME, Sacewicz-Hofman I, et al. Cytoskeleton reorganization in EndMT-the role in cancer and fibrotic diseases. Int J Mol Sci, 2021, 22(21): 11607. doi: 10.3390/ijms222111607.
8. Bourebaba N, Marycz K. Hepatic stellate cells role in the course of metabolic disorders development - A molecular overview. Pharmacol Res, 2021, 170: 105739. doi: 10.1016/j.phrs.2021.105739.
9. Pellinen T, Paavolainen L, Martín-Bernabé A, et al. Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features. J Natl Cancer Inst, 2023, 115(1): 71-82.
10. Jing SY, Liu D, Feng N, et al. Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma. Genome Med, 2024, 16(1): 98.
11. Yang S, Zhang D, Sun Q, et al. Single-cell and spatial transcriptome profiling identifies the transcription factor BHLHE40 as a driver of EMT in metastatic colorectal cancer. Cancer Res, 2024, 84(13): 2202-2217.
12. Zhang K, Liu K, Hu B, et al. Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer. Nat Commun, 2024, 15(1): 9050. doi: 10.1038/s41467-024-53233-1.
13. Liu Y, Chen H, Yan X, et al. MyD88 in myofibroblasts enhances nonalcoholic fatty liver disease-related hepatocarcinogenesis via promoting macrophage M2 polarization. Cell Commun Signal, 2024, 22(1): 86. doi: 10.1186/s12964-024-01489-x.
14. Ma H, Wang J, Zhao X, et al. Periostin promotes colorectal tumorigenesis through integrin-FAK-Src pathway-mediated YAP/TAZ activation. Cell Rep, 2020, 30(3): 793-806.
15. Heichler C, Schmied A, Enderle K, et al. Targeting STAT3 signaling in COL1+ fibroblasts controls colitis-associated cancer in mice. Cancers (Basel), 2022, 14(6): 1472. doi: 10.3390/cancers14061472.
16. Kobayashi H, Gieniec KA, Wright JA, et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology, 2021, 160(4): 1224-1239.
17. Denton AE, Roberts EW, Fearon DT. Stromal cells in the tumor microenvironment. Adv Exp Med Biol, 2018, 1060: 99-114.
18. Sarkar M, Nguyen T, Gundre E, et al. Cancer-associated fibroblasts: the chief architect in the tumor microenvironment. Front Cell Dev Biol, 2023 Jan 30: 11: 1089068. doi: 10.3389/fcell.2023.1089068.
19. van Genderen MNG, Kneppers J, Zaalberg A, et al. Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties. NPJ Syst Biol Appl, 2024, 10(1): 20. doi: 10.1038/s41540-024-00344-6.
20. Yang X, Zheng H, Huang J, et al. Co-inhibition of PGF and VEGFA enhances the effectiveness of immunotherapy in bladder cancer. Int J Med Sci, 2024, 21(15): 2870-2882.
21. Shen Y, Wang X, Lu J, et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell, 2020, 37(6): 800-817.
22. Piwocka O, Piotrowski I, Suchorska WM, et al. Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy. Front Mol Biosci, 2024, 11: 1343523. doi: 10.3389/fmolb.2024.1343523.
23. Lunina NA. , Safina DR, Kostrov SV. Cancer-associated fibroblasts: heterogeneity and bimodality in oncogenesis. Mol Biol (Mosk) 2023, 57 (5), 739-770.
24. Peña C, Céspedes MV, Lindh MB, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res, 2013, 73(4): 1287-1297.
25. Xie Q, Liu X, Liu R, et al. Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer. Mol Cancer, 2024, 23(1): 252. doi: 10.1186/s12943-024-02166-w.
26. Wanandi SI, Hilbertina N, Siregar NC, et al. Cancer-associated fibroblast (CAF) secretomes-induced epithelial-mesenchymal transition on HT-29 colorectal carcinoma cells associated with hepatocyte growth factor (HGF) signalling. J Pak Med Assoc 2021, 71(Suppl 2) (2), S18-s24.
27. Liao J, Chen R, Lin B, et al. Cross-talk between the TGF-β and cell adhesion signaling pathways in cancer. Int J Med Sci, 2024, 21(7): 1307-1320.
28. Bauer J, Emon MAB, Staudacher JJ, et al. Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling. Sci Rep, 2020, 10(1): 50. doi: 10.1038/s41598-019-55687-6.
29. Sun S, Zhang Y, Li Y, et al. Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs. Front Immunol, 2023, 14: 1161628. doi: 10.3389/fimmu.2023.1161628.
30. Tommelein J, De Vlieghere E, Verset L, et al. Radiotherapy-activated cancer-associated fibroblasts promote tumor progression through paracrine IGF1R activation. Cancer Res, 2018, 78(3): 659-670.
31. Peng S, Chen D, Cai J, et al. Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis. Mol Oncol, 2021, 15(5): 1391-1411.
32. Sung PJ, Rama N, Imbach J, et al. Cancer-associated fibroblasts produce Netrin-1 to control cancer cell plasticity. Cancer Res, 2019, 79(14): 3651-3661.
33. Zhao Z, Zhu Y. FAP, CD10, and GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer. BMC Cancer, 2023, 23(1): 507. doi: 10.1186/s12885-023-11011-0.
34. Garvey CM, Lau R, Sanchez A, et al. Anti-EGFR therapy induces EGF secretion by cancer-associated fibroblasts to confer colorectal cancer chemoresistance. Cancers (Basel), 2020, 12(6): 1393. doi: 10.3390/cancers12061393.
35. Chen X, Liu Y, Zhang Q, et al. Exosomal miR-590-3p derived from cancer-associated fibroblasts confers radioresistance in colorectal cancer. Mol Ther Nucleic Acids, 2020, 24: 113-126.
36. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med, 2020, 383(23): 2207-2218.
37. 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. Mol Cancer, 2023, 22(1): 159. doi: 10.1186/s12943-023-01860-5.
38. Arab S, Hasannejad F. An overview of current therapeutic strategies for glioblastoma and the role of CD73 as an alternative curative approach. Clin Transl Oncol, 2022, 24(5): 742-756.
39. Zadka Ł, Chabowski M, Grybowski D, et al. Interplay of stromal tumor-infiltrating lymphocytes, normal colonic mucosa, cancer-associated fibroblasts, clinicopathological data and the immunoregulatory molecules of patients diagnosed with colorectal cancer. Cancer Immunol Immunother, 2021, 70(9): 2681-2700.
40. Bigos KJ, Quiles CG, Lunj S, et al. Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours. Front Oncol, 2024, 14: 1331355. doi: 10.3389/fonc.2024.1331355.
41. Li Z, Zhou J, Zhang J, et al. Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5. Int J Cancer, 2019, 145(7): 1946-1957.
42. Sun D, Tan L, Chen Y, et al. CXCL5 impedes CD8⁺ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis. J Exp Clin Cancer Res, 2024, 43(1): 202. doi: 10.1186/s13046-024-03122-8.
43. Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol, 2021, 18(12): 792-804.
44. Huang L, Lu W, Wu R, et al. Interferon-driven CAF reprogramming augments immunogenic response to neoadjuvant radiotherapy in colorectal cancer. Cell Rep Med, 2025, 6(8): 102251. doi: 10.1016/j.xcrm.2025.102251.
45. Wang H, Lin B, Wang Z, et al. Fusobacterium nucleatum increases CTGF expression through TLR2-YAP signaling axis in cancer-associated fibroblasts, thereby promoting colorectal cancer progression. Cancer Cell Int, 2025, 25(1): 381. doi: 10.1186/s12935-025-04023-2.
46. Chen L, Qiu X, Wang X, et al. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression. Biochem Biophys Res Commun, 2017, 487(1): 8-14.
47. Yuan Q, Gu J, Zhang J, et al. MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization. Cell Rep, 2021, 34(5): 108724. doi: 10.1016/j.celrep.2021.108724.
48. Xie L, Jiang FC, Zhang LM, et al. Targeting of MyD88 homodimerization by novel synthetic inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer. J Natl Cancer Inst, 2015, 108(4): djv364. doi: 10.1093/jnci/djv364.
49. Heichler C, Scheibe K, Schmied A, et al. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut, 2020, 69(7): 1269-1282.
50. Chalikonda G, Lee H, Sheik A, et al. Targeting key transcriptional factor STAT3 in colorectal cancer. Mol Cell Biochem, 2021, 476(9): 3219-3228.
51. Chen CY, Yang SH, Chang PY, et al. Cancer-associated-fibroblast-mediated paracrine and autocrine SDF-1/CXCR4 signaling promotes stemness and aggressiveness of colorectal cancers. Cells, 2024, 13(16): 1334. doi: 10.3390/cells13161334.
52. Kang S, Tanaka T, Narazaki M, et al. Targeting interleukin-6 signaling in clinic. Immunity, 2019, 50(4): 1007-1023.
53. Ghatak S, Hascall VC, Karamanos N, et al. Interplay between chemotherapy-activated cancer associated fibroblasts and cancer initiating cells expressing CD44v6 promotes colon cancer resistance. Front Oncol, 2022, 12: 906415. doi: 10.3389/fonc.2022.906415.
54. Chen K, Kolls JK. Interluekin-17A (IL17A). Gene, 2017, 614: 8-14.
55. Liu Y, Paauwe M, Nixon AB, et al. Endoglin targeting: lessons learned and questions that remain. Int J Mol Sci, 2020, 22(1): 147. doi: 10.3390/ijms22010147.
56. Huang TX, Tan XY, Huang HS, et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut, 2022, 71(2): 333-344.
57. Jacobs J, Deschoolmeester V, Zwaenepoel K, et al. CD70: an emerging target in cancer immunotherapy. Pharmacol Ther, 2015, 155: 1-10.
58. Diep CH, Spartz A, Truong TH, et al. Progesterone receptor signaling promotes cancer associated fibroblast mediated tumorigenicity in ER+ breast cancer. Endocrinology, 2024, 165(9): bqae092. doi: 10.1210/endocr/bqae092.
59. Kono M, Komatsuda H, Yamaki H, et al. Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma. Oncoimmunology, 2022, 11(1): 2021619. doi: 10.1080/2162402X.2021.2021619.

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