The hallmarks of cancer include the complicated progression of tumors that advance to control and stop the body’s normal responses and the existence of human cells that have the capacity to move from a normal condition to a neoplastic state to form malignant tumors ^[1][2]. The hallmark of cancer contains six distinct biological features identified in the course of the multistep progression of human tumors, and this number has since been expanded to eight ^[2]. This represents an organizing basis for rationalizing the complexities of neoplastic diseases. These complexities consist of the following: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. The fundamental reasons for these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, inflammation, and fosters multiple hallmark functions. Scientific progress within the last decade has revealed two emerging hallmarks of potential generality that can be added to the present list: the reprogramming of energy metabolism and the evasion of immune destruction ^[3]. The variety of tumor hallmarks has been defined in different ways by various researchers. Here, the immune evasion, which is known to be an important hallmark in solid tumors ^[4]. Tumors are surrounded by a tumor microenvironment (TME), which is an extremely complicated ecosystem. Tumor cells interact with immune cells (including macrophages, poly-morphonuclear cells (PMN), mast cells, natural killer (NK) cells, dendritic cells (DCs), and T and B lymphocytes), and non-immune cells (which include endothelial cells and stromal cells) and demonstrate sophisticated interactions with these that regulate the tumor’s natural behaviors. In particular, the immune cells’ components are essential in delineating the tumor’s destiny, their invasive character, and their metastatic capacity. A wide range of different types of immune cells may infiltrate into the tumor, and their formation and organization inside the TME are closely related to the clinical results of patients who struggle with different cancers ^[5]. The mission of these immune cell types in tumor growth and progression is numerous and is closely related to their inherent functions and to the molecules they express ^[6]. Moreover, TME includes non-malignant tumor cells such as cancer-associated fibroblasts (CAFs), endothelial cells and pericytes composing tumor angiogenesis, immune and inflammatory cells, bone marrow-derived cells, and the extracellular matrix (ECM) organizing a sophisticated cross-talk with tumor cells ^[7].

Immune escape characterized by an incapacitated immune system for the eradication of transformed cells is the hallmark of carcinogenesis ^[8][9]. There exist proteases such as protein convertases (PCs) that interfere in the activation of almost all proteins. Mutations in proteases and/or abnormal protease activity are significantly correlated with several pathological problems such as cancer, Alzheimer’s disease, cardiovascular disorders, and autoimmune diseases ^[10]. Post-translational changes are paramount strategies that contribute to the biological functions of proteins. One such modification is the endo-proteolysis of precursor proteins, resulting in activation, inactivation, or functional changes ^[11]. This cleavage procedure can be general or restricted to a few bonds through particular convertases and is followed by amino-terminal, internal, and carboxy-terminal modifications into smaller biologically active polypeptides ^[12][13]. Proprotein convertases (PCs) are a family of nine serine proteases involved in the processing of cellular pro-proteins. They induce the activation, inactivation, or functional changes in numerous proteins such as neuropeptides, hormones, receptors, and growth factors. Therefore, these enzymes are fundamental for cellular balance in health and disease. Nine PC subtilisin/kexin genes (PCSK1 to PCSK9) encoding for PC1/3, PC2, Furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9 are known. The expression of PC1/3, PC2, PC5/6, Furin, and PC7 in lymphoid organs such as lymph nodes, thymus, and spleen has been found to play a role in these enzymes regarding immunity ^[14]. Proprotein convertases are in the group of proteases that cleave proteins and turn them into their active or inactive form. Several of their substrates are involved in tumorigenesis and immune suppression ^[15].

2. The Role of the Immune System in the TME

The immune system is a complicated set of cells, tissues, and organs. They work together to preserve organisms from dangerous substances, pathogens, and tissue damage and to stop the event of diseases. The immune system has been categorized into innate and adaptive immunity based on variations in the activation of immune responses to many threats ^[16]. Immune cells are a part of the tumor microenvironment (TME) and the communication between immune cells, other TME cells, and cancer cells plays a principal role in tumor development. Tumors exist in a complex microenvironment in which several kinds of cells can be found ^[17]. All kinds of immune cells can be found in tumor microenvironments including macrophages; dendritic cells (DCs); mast cells; natural killer (NK) cells; naive and memory lymphocytes B cells; effector T helper (Th) cells including: Th1 cells, Th2 cells, and Th17 cells; regulatory T (Treg) cells; T follicular helper (TFH) cells; and T cytotoxic (TC) cells ^[18]. These immune cells may be located in the center of the tumor, in the invasive margin, or close to tertiary lymphoid structures (TLSs). Inflammatory and immune cells liberate growth factors (GFs) such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF-A/C), fibroblast growth factor (FGF2), as well as different cytokines amplifying inflammatory conditions, and enzymes degrading the extracellular matrix, which include MMPs (matrix metalloproteinases), cathepsin, and heparinases ^[18]. In addition, these cells secrete TGF-B and IL-10, which are associated with immunosuppression by activating and recruiting regulatory T cells (Treg) into the tumor ^[19][20]. At first, TGF-B1 controls the Th1 and Th2 balance in favor of Th2 phenotypes without cytotoxic activity against the tumor. TGF-B then constrains Th1 response and M1-type macrophage activity; suppresses lymphocytes CD8+, natural killer (NK) cells, and dendritic cell (DC) function; generates Treg with immunosuppressive function; and promotes M2-type macrophages with pro-tumor activity ^[19][20]. Regulatory T cells are one of the most striking immunosuppressive subsets of CD4+ (CD25+) T cells; they are primarily regulated by master transcription factor 3 (FOXP3), and they account for approximately 5% of the total CD4+ T cell population under conventional circumstances ^[21]. Tregs, as a prominent mechanism for the controlling equilibrium of the immune system and the immune tolerance of the body, play an essential role in regulating tumor immunity, and they can hinder the activation and differentiation of CD4+ helper T cells and CD8+ cytotoxic T cells to promote reactivity against autologous and tumor-expressed antigens ^[22][23][24]. In the TME, Tregs can be stimulated and differentiated by conventional T cells, which have a powerful immunosuppressive function, inhibit antitumor immunity, and induce the incidence and development of tumors. Tregs can also suppress the mission of immune effector cells through numerous mechanisms and are key factors in tumor immune escape ^{[25][26][27][28]}. The TME provides a suppressive action on Tregs by the overexpression of immune checkpoint (IC) molecules. Targeting IC molecules on Tregs may be effective for cancer treatment. Some of the most important IC molecules are CTLA-4, TIGIT, PD-1 (programmed cell death protein 1), and GITR ^[29]. Regulatory CD4+ T lymphocytes (Treg) directly secrete or facilitate the formation of immunosuppressive molecules (e.g., IL-10 and adenosine), and modulate the Ag presenting cells (APCs) function (e.g., via CTLA-4–CD80/86 interactions) ^[30]. Regarding macrophages in the TME, they are in the group of myeloid cells that have many type of phenotypes in which the M1 or M2 subclasses are the most important. The function of M1 macrophages in immunity against tumors is that M1 cells are “classically activated” by IFNγ, and annihilate tumor cells via their production of nitric oxide (NO) and type 1 cytokines and chemokines. Moreover, M1 acts as an APC, activating cytotoxic CD8+ T cells in an antigen (Ag)-specific manner. Another subcategory is M2 macrophages. M2 cells are activated by “alternative” pathways through IL-4, IL- 13, and/or TGFβ. In tumor immunity M2 has a different action in comparison with the M1 type. M2 releases type 2 chemokines and cytokines; as a result, they elevate the growth of tumors and progression. In the TME, stromal and tumor-associated factors can shift macrophages to the M2 phenotype that are known as polarization, particularly the type of tumor-associated macrophages (TAMs) that promote tumor progression, angiogenesis, and metastasis ^[31]. Consequently, some immune cells often illustrate flexibility in the TME, demonstrating both tumor-promoting and tumor-hindering potential. For instance, while some macrophages (M1) predominately generate pro-inflammatory cytokines that ensure the anti-tumor immune response, others (M2) can induce the proliferation of fibroblasts, ECM degradation, and immunosuppression ^[32]. Moreover, tumor-promoting M2 macrophages accompany other cells to enhance tumor progression, such as immature granulocytic and monocytic cells (myeloid-derived suppressor cells (MDSCs)) that can accelerate tumor progression via elevating the proliferation of stromal cells, causing angiogenesis, deposition of extracellular matrix (ECM), and cell migration ^[33][34][35]. The presence of cytotoxic CD8+ memory T cells in the TME, similar to other immune system cells, destroys tumor cells by identifying neo-antigens (specific antigens on the tumor cells) and provoke an immune response that follows a prototypical, tri-phasic pathway(activation, proliferation, and differentiation of cells). CD8+ T cells in the TME are mainly assisted by CD4+ T helper 1 (TH1) cells that secrete interleukin-2 (IL-2) and interferon-gamma (IFN-γ). Further subclasses of CD4+ cells, for example TH2 cells, collaborate in the B cell response by producing IL-4, IL-5, and IL-13. TH17 cell in the group of the CD4+ subpopulation T cells, on the contrary, generate IL-17A, IL-17F, IL-21, and IL-22, which induce tumor proliferation by favoring tissue inflammation ^[36]. The influence of the TME on tumor expansion has also been considered according to the impact of B lymphocytes in innate natural killer T (NKT) and natural killer (NK) cells. B lymphocytes normally exist in the draining lymph nodes lymphoid structures neighboring the TME and the invasive tumor margin. The B lymphocytes in the TME play crucial roles in both the control of tumor cell maintenance and the increase in the occurrence of treatment resistance. In brief, these cells have been identified as playing a role in the stimulation of immune escape ^[36]. Another part of the immune system in the TME is cytokines. Accordingly, it was previously mentioned that these have a close relation with almost all cells as messengers. They are released or membrane-bound proteins that carry out the proliferation, differentiation, and initiation of immune cells. Therefore, uncontrolled cytokine generation is considered to be an important factor in the progression of disorders, for instance, autoimmune diseases and cancer ^[6][37]. Cytokines can carry out various biological functions of cells, including proliferation, differentiation, and migration. Cytokines that have a weight of up to 70 kDa are identified as small proteins ^[38]. Based on their construction and mission, they have been categorized into definite super-families, which include interferons (INFs), interleukins (ILs), tumor necrosis factors (TNFs), transforming growth factors (TGFs), chemotactic cytokines (chemokines), and colony-stimulating factors (CSFs) ^[39]. Within the TME, cytokines can form a tumor-supportive immune microenvironment that suppresses anti-tumor immunity and exerts direct tumor-promoting signals; in contrast, some of them can promote immune escape ^[40]. In contrast to tumor immune escape (TIE), there is tumor immune surveillance(TIS), in which the immune system recognizes precancerous or cancerous cells and removes them before they can create harm ^[41]. Additionally, the importance of immune surveillance has been demonstrated in some research. The major molecules involved in tumor immune surveillance, as recognized in knockout mouse models, consist of interferon-g (IFNg); perforin; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); IL12 and its contributing apoptosis-inducing receptors DR4 and DR5; the recombination activating genes RAG1 and RAG2, which are critical for T cell development; the T cell receptor; and the activating NK cell receptor NKG2D ^[42]. A deficiency of any of these proteins can lead to more frequent or faster tumor immune escape and more tumorigenesis ^[43].