Editorial: Novel Targets and Targeting Technologies to Modulate Tumor Microenvironment

In recent years, there is an increasing attention on the impact of the tumor microenvironment (TME) on tumor initiation, progression, and metastasis (1). Malignant tumor cells and non-malignant stromal cells actively interact with each other and thereby create a tumor-supportive microenviron-ment (2). TME is composed of extracellular matrix and several cell types, such as cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, tumor-associated macrophages (TAMs), and other immune cells (1, 3). The literature has been continuously highlighting new aspects on the complexity of these cell types and their pro-and anti-tumorigenic roles in cancer. For instance, depletion of stroma in pancreatic cancer has been shown to induce tumor growth (4), in contrast to literature showing tumor-promoting effects of stroma (2). There is a continuous increase in revelations of novel cellular and extracellular targets in TME, such as new receptors, extracellular matrix, and microRNA (miRNAs). Modulation of these targets may lead to the development of new diagnostics and thera-peutics for cancer. To reinforce these developments, it is crucial to involve targeting technologies, such as drug and gene-targeting technologies, to TME. Ehnman and Larsson have reviewed the microenvironmental targets in sarcomas, which are rare malignant tumors in all age groups. Treatment of sarcoma has faced several failures in clinical trials, urging a need for developing novel targeted therapies in combination with current multimodality regimens. Vasculature cells (e.g., endothelial cells, pericytes), immune cells (e.g., M2-like mac-rophages, lymphocytes), and fibroblast-like cells are the crucial stromal cells in sarcomas. In clinic, therapies have been focused on inhibiting angiogenesis (e.g., tyrosine kinase inhibitors, including VEGFRs, PDGFRs, and c-KIT) and immune modulation (e.g., monoclonal antibodies against RANK receptor). Several therapies that are under investigation focus on the inhibition of multiple kinases simultaneously. Kuninty et al. highlight miRNAs as key therapeutic targets in TME. miRNAs, small endogenous non-protein-coding RNAs, are emerging as key molecules in the modulation of TME due to their capacity to control cellular processes by inhibiting the expression of multiple target genes. The review enlists miRNAs dysregulated in different stromal cells, including CAFs, TAMs, immune cells, and tumor vascular cells (endothelial cells, pericytes). Due to the inherent physicochemical properties of miRNA (negative charge and hydrophilicity), they cannot pass through the cell membrane. Therefore, novel miRNA delivery systems are crucial to develop in order to target miRNA/anti-miRNA into stromal cells. Delivery strategies based on non-viral delivery systems, such as liposomes, lipoplexes, and polyplexes, are the state-of-the-art carriers to deliver …