Received: 17 July 2018 | Accepted: 22 August 2018 DOI: 10.1002/jcp.27425 REVIEW ARTICLE Tumor microenvironment: Interactions and therapy Masoud Najafi 1 | Nasser Hashemi Goradel 2 | Bagher Farhood 3 | Eniseh Salehi 4 | Somaye Solhjoo 4 | Heidar Toolee 4 | Ebrahim Kharazinejad 5 | Keywan Mortezaee 6 1 Department of Radiology and Nuclear Medicine, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran 2 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Radiology and Medical Physics, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran 4 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 5 Department of Anatomy, Abadan School of Medical Sciences, Abadan, Iran 6 Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran Correspondence Keywan Mortezaee, Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj 66177‐13446, Iran. Email: keywan987@yahoo.com; mortezaee.k@muk.ac.ir Abstract Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer. KEYWORDS cancer‐associated fibroblast, cancer cell, cytotoxic T lymphocyte, exosome, extracellular matrix, hypoxia, immunosuppression, interaction (cross‐talk), regulatory T, tumor microenvironment, tumor‐associated macrophage 1 | INTRODUCTION Cancer remains a main threat for public health and one of the leading causes of death in the world. Most of the conventional chemother- apeutic drugs developed so far only display a narrow therapeutic window due to their inability to distinguish cancer cells from normal cells (Qiao et al., 2018). Deep insight knowledge into tumor microenvironment (TME) provides an opportunity to know more about tumor habits and to pursue more specific strategies in controlling drug delivery for cancer therapeutic purposes (Qiao et al., 2018). TME is a dynamic (Alamoud & Kukuruzinska, 2018) and an acidified (Fels, Bulk, Pethő, & Schwab, 2018) heterocellular place (Reina‐Campos, Shelton, Diaz‐Meco, & Moscat, 2018) that deter- mines cancer fate (Yue, Nguyen, Zellmer, Zhang, & Zorlutuna, 2018) and is responsible for either success or failure of cancer‐targeted therapies (Ghalamfarsa et al., 2018). In fact, critical interactions that occur within this milieu play key roles in altering tumor fate (Buenrostro et al., 2018) into either progression (Fels et al., 2018) or suppression (Iriondo et al., 2018). The TME is actually a special niche for innutrition, acidity, hypoxia, and ischemia (Xiang et al., 2018). Acidity (pH 6.5–6.8) in the TME is an inducer of tumor activation (Xiong, Zhou, Yan, Miller, & Siegwart, 2018) and a target for cancer therapy through controlling drug release inside cancer cells and reducing tolerance in the cells (Qiao et al., 2018). Dynamic changes that occur within the TME are associated with cancer cell plasticity (Alamoud & Kukuruzinska, 2018) in which blocking one pathway in the TME promotes the others (F. Zhang, Stephan, et al., 2018). These dynamic changes along with compensa- tory mechanisms eventually enable cancer cells to develop resistance J Cell Physiol. 2019;234:5700–5721. wileyonlinelibrary.com/journal/jcp 5700 | © 2018 Wiley Periodicals, Inc.