Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer

Abstract

Cancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest in the field of anticancer therapy: immunotherapy, metabolism, and extracellular vesicles. We also highlight the substantial role of CAFs in modulating the immune microenvironment and the recent advances in targeting CAFs for cancer treatment.

Figure 1. The complex microenvironment of solid tumors.

Schematic representation of cells and structures comprising the TME. To grow, cancer cells subvert the surrounding tissue microenvironment and utilize blood vessels, lymphatic vessels, and nerves to metastasize to secondary sites. Stromal and immune cells are key players of tumor progression and can have tumor-restraining or tumor-promoting functions depending on the context. Cancer and TME cells secrete a plethora of proteins, ECM components, metabolites and EVs to establish local and systemic communication networks with the TME. DCs: dendritic cells; MDSCs: Myeloid-derived suppressor cells. Created with Biorender.

Figure 2. Metabolic pathways influencing myCAF and iCAF phenotypes in cancer.

Created with Biorender.

Figure 3. CAFs modulate the immune microenvironment.

a – CAFs themselves and their ECM can create a physical barrier that hinders the infiltration of T cells. Different subsets of CAFs promote T cell marginalization in early versus late-stage lung tumors through secretion of specialized matrix. b - Subsets of CAFs can have tumor-promoting or tumor-restraining functions towards T and NK cell functions. CAFs can alter the biology of cytotoxic T cells, effector CD4+, regulatory T cells, T helper 17 cells and NK cells. c – Subsets of CAF exploit distinct mechanisms to recruit and remodel the myeloid compartment, ultimately creating an immunosuppressive TME. d – Distinct subsets of CAFs can either support or impair the efficacy of immunotherapy. Mechanisms depicted in the figure are those discussed in the text from recent literature. Created with Biorender.

Figure 4. Emerging areas of interest in the field of CAF biology.

We highlight the translational opportunities in investigating CAF biology in the context of metabolism, immune TME, extracellular vesicles, and microbiome. We anticipate that the advancement in cutting-edge technologies, such as single cell proteomics and MSI, will revolutionize our understanding of CAF biology in the upcoming years. New therapeutic avenues focused on targeting CAFs, alone or in combination with existing anti-cancer therapies, such as immunotherapy, chemotherapy and radiotherapy are also becoming popular. Created with Biorender.