Fibroblast diversity and plasticity in the tumor microenvironment: roles in immunity and relevant therapies

Abstract

Cancer-associated fibroblasts (CAFs), enriched in the tumor stroma, have received increasing attention because of their multifaceted effects on tumorigenesis, development, metastasis, and treatment resistance in malignancies. CAFs contributed to suppressive microenvironment via different mechanisms, while CAFs also exerted some antitumor effects. Therefore, CAFs have been considered promising therapeutic targets for their remarkable roles in malignant tumors. However, patients with malignancies failed to benefit from current CAFs-targeted drugs in many clinical trials, which suggests that further in-depth investigation into CAFs is necessary. Here, we summarize and outline the heterogeneity and plasticity of CAFs mainly by exploring their origin and activation, highlighting the regulation of CAFs in the tumor microenvironment during tumor evolution, as well as the critical roles performed by CAFs in tumor immunity. In addition, we summarize the current immunotherapies targeting CAFs, and conclude with a brief overview of some prospects for the future of CAFs research in the end. Video Abstract.

Keywords: Cancer-associated fibroblasts; Heterogeneity; Immunotherapies; Plasticity; Targeted therapies.

Fig. 1

Origins, Activation of CAFs and General functions. Schematic description of various mechanisms involved in activation and general functions of CAFs. Potential cellular origins of CAFs include quiescent fibroblasts and stellate cells, bone marrow-derived mesenchymal stem cells (MSCs), adipocytes and other cell types. ECM, extracellular matrix; ROS, reactive oxygen species; DAMPs, damage associated molecular patterns

Fig. 2

Modulation of CAFs. The variables and possible potential mechanisms that affect the alteration of CAFs in the microenvironment are briefly summarized. The morphology and function of CAFs vary as the tumor progression due to numerous variables in the tumor microenvironment. Cancer cells can modulate CAFs by releasing chemical compounds, altering metabolisms and epigenetic modification. Similarly, regulatory molecules released by inflammatory cells also have an impact on CAFs. Besides, the extracellular matrix exerts a great regulatory effect on CAFs

Fig. 3

Regulation of CAFs on immune cells. CAFs can orchestrate an immunosuppressive TME by interacting with the immune cells in tumors. By secreting a variety of chemokines, cytokines and other effector molecules, such as TGF- β, IL-6, C-X-C chemokine ligand 12 (CXCL12), C–C-C chemokine ligand 2 (CCL2), SDF-1, vascular endothelial growth factor (VEGF), indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2), CAFs regulate immune cells-mediated anti-tumor immunity in tumor microenvironment via triggering multiple pathways

Fig. 4

Principal strategies for targeting CAFs. The primary anticancer agents that target the stromal compartment in malignancies are printed. The activation or functions of CAFs can be inhibited by targeting important signals and effectors of CAFs, such as chemokine and growth factor pathways. Moreover, either transgenic technologies or immunotherapies can directly deplete CAFs. Through the application of chemicals like vitamin A or vitamin D, CAFs can also be adjusted to an inactive phenotype. Finally, it is viable to target CAFs-derived extracellular matrix proteins and related signaling to deplete the stroma and boost immunological T cell infiltration