1. Tumor microenvironment (TME)
The tumor microenvironment (TME) provides a secure environment for cancer cells to evade the desired outcomes of various treatments. Essentially, the TME is a complex and dynamic ecosystem composed of diverse factors that play crucial roles in inhibiting apoptosis, proliferation, migration, immune evasion, treatment resistance, metastasis, metabolic reprogramming, and all stages of tumorigenesis [5]. The tumor microenvironment factors are generally divided into two main components: cellular components (such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and endothelial cells (ECs) which all of them are stromal cells), and non-cellular components (such as growth factors, various chemokines and cytokines, interstitial fluids, metabolites, extracellular matrix (ECM) and exosomes) [5, 6]. Therefore, targeting the TME is a potentially effective strategy for achieving fruitful outcomes of cancer therapy, and small molecules can easily penetrate the TME and ultimately reach tumor cells and affect them [6]. The tumor microenvironment is a hypoxic and low-pH environment [6]. The rapid growth of tumor cells causes hypoxia, which subsequently causes the release of stimulating factors such as vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and hypoxia-inducible factor-1α (HIF- 1α) [5]. Also, the condition of hypoxia in TME affects the endothelial cells by secreting angiogenic factors from the tumor and subsequently promoting angiogenesis [7, 8]. In the TME, the most abundant stromal cells are cancer-associated fibroblasts (CAFs) that can produce abnormal extracellular matrix (ECM) which supports tumor cell migration [9]. TME reshaping creates the conditions for tumor cells to interact with surrounding fibroblasts, immune cells, and endothelial cells, leading to the induction of a variety of biological events, including angiogenesis, migration, proliferation, immune system suppression, and drug resistance, which ultimately causes tumor growth [9-18].
One of the important events in the TME is cell interaction and cell communication with the ECM because this interaction causes the release of factors that play a role in ECM remodeling and immune evasion, which ultimately strengthens treatment resistance [19]. Other important events are the generation of exosomes by benign and malignant cells, TME-specific metabolic patterns, and circulating deregulated microRNAs that increase treatment resistance [19]. There are many different types of immune cells in the TME that block the immune response, in addition, around the tumor cells, there are a set of inflammatory molecules that cause the failure to identify and eliminate cancer cells by the immune system, which together make TME a complex and heterogeneous space and they often cause an uncontrollable process in the growth and development of tumors [5, 20-24]. On the whole, a wide range of events and factors from biochemical agents, and a hypoxic environment to abnormal mechanical forces cause treatment resistance [19]. In the following, circumstances and various components of the tumor microenvironment are discussed: