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Fibroblasts form diverse subtypes that can modulate immune cell proportions, promote or suppress tumor growth, create pre-metastatic niches, and remodel the extracellular matrix. Their pro- and anti-tumor phenotypes vary across cancer entities and within individuals, including primary and metastatic sites. In addition, renin–angiotensin system inhibitors can affect fibroblasts, altering immune fractions and increasing tissue stiffness, which may influence therapy resistance. 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Bruns 1 and Thomas Schmidt 1, *  \nCitation: Knipper, K.; Lyu, S.I.; Quaas, A.; Bruns, C.J.; Schmidt, T. Cancer-Associated Fibroblast Heterogeneity and Its Influence on the Extracellular Matrix and the Tumor Microenvironment. Int. J. Mol. Sci. 2023, 24, 13482. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms241713482](10.3390/ijms241713482)  \nAcademic Editor: Karel Smetana, Jr.  \nReceived: 31 July 2023  \nRevised: 24 August 2023  \nAccepted: 28 August 2023  \nPublished: 30 August 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany; [karl.knipper@uk-koeln.de](karl.knipper@uk-koeln.de) (K.K.); [christiane.bruns@uk-koeln.de](christiane.bruns@uk-koeln.de) (C.J.B.)  \n2 Institute of Pathology, University Hospital of Cologne, Faculty of Medicine, University of Cologne,  \n50937 Cologne, Germany; [su.lyu@uk-koeln.de](su.lyu@uk-koeln.de) (S.I.L.); alexander.quaas@uk-koeln.de (A.Q.)  \n* Correspondence: [thomas.schmidt1@uk-koeln.de](thomas.schmidt1@uk-koeln.de)  \nAbstract: The tumor microenvironment comprises multiple cell types, like cancer cells, endothelial cells, fibroblasts, and immune cells. In recent years, there have been massive research efforts focusing not only on cancer cells, but also on other cell types of the tumor microenvironment, thereby aiming to expand and determine novel treatment options. Fibroblasts represent a heterogenous cell family consisting of numerous subtypes, which can alter immune cell fractions, facilitate or inhibit tumor growth, build pre-metastatic niches, or stabilize vessels. These effects can be achieved through cell–cell interactions, which form the extracellular matrix, or via the secretion of cytokines or chemokines. The pro-or antitumorigenic fibroblast phenotypes show variability not only among different cancer entities, but also among intraindividual sites, including primary tumors or metastatic lesions. Commonly prescribed for arterial hypertension, the inhibitors of the renin–angiotensin system have recently been described as having an inhibitory effect on fibroblasts. This inhibition leads to modified immune cell fractions and increased tissue stiffness, thereby contributing to overcoming therapy resistance and ultimately inhibiting tumor growth. However, it is important to note that the inhibition of fibroblasts can also have the opposite effect, potentially resulting in increased tumor growth. We aim to summarize the latest state of research regarding fibroblast heterogeneity and its intricate impact on the tumor microenvironment and extracellular matrix. Specifically, we focus on highlighting recent advancements in the comprehension of intraindividual heterogeneity and therapy options within this context.  \nKeywords: fibroblasts; myofibroblasts; iCAFs; eCAFs; pericytes; extracellular matrix; targeted therapy  \n1. Introduction  \nDespite massive research efforts, cancer remains a global healthcare challenge. Projections anticipate that, in the year 2022 alone, in the United States of America, around two million patients were diagnosed with cancer, and 609,360 patients suffered cancer-related deaths [1] . Published in 2000, Hanahan et al. introduced the hallmarks of cancer, which represent the main acquired capabilities for the progression of cancer known at that time [2] . Over twenty years later, due to extensive research, this list","cbCainq2SDpvgwSH","https://ap.wps.com/l/cbCainq2SDpvgwSH","pdf",1218607,21,"English","# Introduction\n## Tumor microenvironment and cancer hallmarks\n## Fibroblasts as heterogeneous cell family\n## Effects on extracellular matrix and immune composition\n## Intraindividual heterogeneity and therapy options","[{\"question\":\"What is the role of fibroblast heterogeneity in the tumor microenvironment?\",\"answer\":\"Fibroblast subtypes can alter immune cell fractions, promote or inhibit tumor growth, and help form pre-metastatic niches. Their effects are mediated through extracellular matrix formation and cytokine or chemokine secretion.\"},{\"question\":\"How do fibroblasts influence the extracellular matrix?\",\"answer\":\"Fibroblast–cell interactions and secretion of signaling molecules contribute to building and remodeling the extracellular matrix. This remodeling links fibroblast phenotypes to changes in tissue properties.\"},{\"question\":\"Why can renin–angiotensin system inhibitors affect tumor progression?\",\"answer\":\"These inhibitors have been described as modulating fibroblast activity, which can change immune cell fractions and increase tissue stiffness. The review also notes that fibroblast inhibition may sometimes produce the opposite effect and potentially increase tumor growth.\"}]","Cancer-Associated Fibroblast Heterogeneity and Its Influence on the Extracellular Matrix and the Tumor Microenvironment | PDF",1790272929,53]