Friend or foe: The paradoxical roles of cancer-associated fibroblasts in tumour immunotherapy

Abstract

Cancer-associated fibroblasts (CAFs) represent critical cellular components of the tumor microenvironment and have garnered widespread attention in the field of tumor immunology. However, given the pronounced heterogeneity of CAFs, research investigating their impact on tumor immunity has yielded diverse and often contradictory results. Therefore, in this review, we have systematically summarized previous studies to comprehensively elucidate the role of CAFs in the tumor immune microenvironment and have explored the bidirectional regulatory effects of CAFs on immune cells and immune molecules within this complex niche. We highlight the multifaceted role of CAFs in cancer immunotherapy, focusing on their impact on immunotherapeutic efficacy, as well as the synergistic effects between CAF-targeted therapies and immunotherapies in anti-cancer treatment. Addressing the heterogeneity of CAFs, we also critically analyze controversies surrounding these cells in the field of tumor immunology and propose strategic directions for future investigations targeting this cell population. Our comprehensive analysis provides a strategic framework for future research directions and clinical translation of CAF-targeted strategies, ultimately facilitating the development of more effective and personalized cancer immunotherapeutic approaches.

References

[1] Arpinati L, Carradori G, Scherz-Shouval R. CAF-induced physical constraints controlling T cell state and localization in solid tumours. Nat Rev Cancer. 2024; 24(10): 676-693.

[2] Liu T, Han C, Wang S, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019; 12(1): 86.

[3] Mao X, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumour microenvironment: new findings and future perspectives. Mol Cancer. 2021; 20(1): 131.

[4] Pei L, Liu Y, Liu L, et al. Roles of cancer-associated fibroblasts (CAFs) in anti-PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer. 2023; 22(1): 29.

[5] Zhang H, Yue X, Chen Z, et al. Define cancer-associated fibroblasts (CAFs) in the tumour microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials. Mol Cancer. 2023; 22(1): 159.

[6] Tauriello DVF, Sancho E, Batlle E. Overcoming TGFβ-mediated immune evasion in cancer. Nat Rev Cancer. 2022; 22(1): 25-44.

[7] Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020; 17(8): 487-505.

[8] Zhang H, Liu Y, Liu J, et al. cAMP-PKA/EPAC signaling and cancer: the interplay in tumour microenvironment. J Hematol Oncol. 2024; 17(1): 5.

[9] Bhat AA, Nisar S, Singh M, et al. Cytokine- and chemokine-induced inflammatory colorectal tumour microenvironment: emerging avenue for targeted therapy. Cancer Commun (Lond). 2022; 42(8): 689-715.

[10] Lin Z, Li G, Jiang K, Li Z, Liu T. Cancer therapy resistance mediated by cancer-associated fibroblast-derived extracellular vesicles: biological mechanisms to clinical significance and implications. Mol Cancer. 2024; 23(1): 191.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.