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. 2021 Oct 11;20:131. doi: 10.1186/s12943-021-01428-1

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 2 — Crosstalk between cancer-associated fibroblasts (CAFs) and immune components in the tumor immune microenvironment (TIME). CAFs can orchestrate an immunosuppressive TME via interacting with the immune microenvironment in tumor. Through the secretion of multiple chemokines, cytokines and other effector molecules such as transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), C-X-C chemokine ligand 12 (CXCL12), C–C chemokine ligand 2 (CCL2), stromal-derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF) along with indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2), CAFs modulate immune cells-mediated antitumor immunity through the following pathways: Promoting the trans-differentiation or polarization of immune cells such as tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), mast cells (MCs), dendritic cells (DCs) and T lymphocytes into certain protumorigenic cell subsets; Facilitating the activities of immune inhibitory cells in terms of recruitment, activation and immunosuppressive effects including M2-type TAMs, N2-type TANs, regulatory DCs (rDCs), regulatory T(Treg) cells and myeloid-derived suppressor cells (MDSCs); Restricting the cytotoxic activity and cytokines production of effector immune cells like natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Notably, several infiltrating immune cells such as TAMs, TANs, MCs and DCs can in turn exert promoting effect on CAFs activation and function, thereby contributing to the formation of immune suppressive loops. Moreover, CAFs can also upregulate the expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1)/programmed death receptor ligand-1 (PD-L1) and cytotoxic T lymphocyte associate protein-4 (CTLA4)/B7 in both themselves and other cells in the TME to induce T-cells dysfunction. Meanwhile, CAFs are able to remodel extracellular matrix (ECM) to facilitate immune suppression through the production of fibronectin, collagen and metalloproteinases (MMPs) as well as the activation focal adhesion kinase (FAK) signaling pathway. Finally, immune checkpoint molecule overexpression on CAF surface as well as matrix deposition around would inhibit CAF apoptosis and facilitate their activation and function