Therapeutic Targeting of the Tumor Microenvironment

Abstract

The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing therapeutic outcome is now widely appreciated, and multiple therapies directed to various components of the TME have been developed in recent years. In this review, we will introduce the key cell types and features of the TME; discuss how these can be therapeutically targeted, with an emphasis on therapies that are under clinical evaluation or have been approved; highlight how the TME is altered by various interventions including standardof-care therapies; and conclude with an overview of the opportunities and potential challenges to consider in the coming years.The TME is defined as the complex and rich multicellular environment in which a tumor develops. The TME typically comprises immune cells, including T and B lymphocytes, tumor-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, neutrophils, and myeloid-derived suppressor cells (MDSC); stromal cells such as cancer-associated fibroblasts (CAF), pericytes, and mesenchymal stromal cells; the extracellular matrix (ECM) and other secreted molecules, such as growth factors, cytokines, chemokines, and extracel-absTRaCT Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field.Significance: This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.Research.

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

“…Tumors are surrounded by several non-cancerous components, including fibroblasts, immunocytes, adipose cells, blood vessels composed of endothelial cells and pericytes, extracellular matrix, infiltrated nerves and a variety of soluble molecules, such as chemokines, interleukins, lactate and vascular endothelial growth factor (VEGF). These factors have been associated with tumor cells and form the tumor microenvironment (TME), which provides an essential foundation to support the growth, metabolic reprogramming, immunosuppressive abilities, metastasis, recurrence and treatment resistance of malignant tumors (2,3). In the past decade, an increasing number of studies have highlighted the importance of the interactions between the TME and tumor cells (4)(5)(6) and targeting the tumor stroma has emerged as a novel cancer treatment paradigm (3,4,7).…”

“…These factors have been associated with tumor cells and form the tumor microenvironment (TME), which provides an essential foundation to support the growth, metabolic reprogramming, immunosuppressive abilities, metastasis, recurrence and treatment resistance of malignant tumors (2,3). In the past decade, an increasing number of studies have highlighted the importance of the interactions between the TME and tumor cells (4)(5)(6) and targeting the tumor stroma has emerged as a novel cancer treatment paradigm (3,4,7). However, the molecular mechanisms underlying the interactions between tumor cells and the TME are complicated and the interactions between different types of stromal cells in the TME remain unknown.…”

Stimuli-Responsive Polymeric Nanoplatforms for Cancer Therapy

“…In addition, abnormal physiological environments, such as acidic extracellular pH and hypoxia, also play key roles in cancer progression, metastasis and drug resistance (Spill et al, 2016;Wang Y.A. et al, 2018;Bejarano et al, 2021; Figure 2). For example, the extracellular pH in tumor tissues is more acidic (5.7-6.9) than in the blood pH (7.4) at 37 • C (Alfarouk et al, 2011).…”

Uncovering of the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

“…Recently, targeting the TME has been an encouraging method for cancer treatment [13]. Some studies showed a correlation between RNA modi cation and TME-in ltrating immune cells [14][15][16][17].…”