## 4 Cellular Component of the CRC microenvironment
### Tumor-Associated Macrophages (TAMs)  
Macrophages are immune cells with diverse phenotypes and functions. Their primary role involves the maintenance of homeostasis, tissue repair, and contribution to the non-specific immune response against pathogens [91]. These functions are attributed to their phagocytic abilities and the ability to activate and recruit immune-competent cells [92]. In the TME, TAMs play a complex role that is different from primary macrophages. Due to their plasticity, TAMs can undergo polarization that changes their phenotype and functions [93]. This means that they have a dualistic nature. Adoption of the M1 phenotype (considered anti-cancer) to the pro-cancer M2 phenotype depends on the stage of the tumor  
Figure 1: Interactions between CRC cells and TME components. Arg: arginase; bFGF: basic fibroblast growth factor; CAF: cancer-associated fibroblast; CCL: C–C motif chemokine ligand; CXCL\(-\)12: C–X–C motif chemokine ligand\(-\)12; EC: endothelial cell; EGF: epidermal growth factor; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IGFBP2: insulin\(-\)like growth factor binding protein\(-\)2; IL: interleukin; iNOS: inducible nitric oxide synthase; LOX: lysyl oxidase; MMP: matrix metalloproteinase; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase; ONOO\(-\): peroxynitrite; PDGF: platelet\(-\)derived growth factor; PGE2: prostaglandin E2; ROS: reactive oxygen species; TAM: tumor\(-\)associated macrophage; TGF\(-\beta\): transforming growth factor \(\beta\); TIL: tumor\(-\)infiltrating lymphocyte; TNF: tumor necrosis factor; IPA: tissue plasminogen activator; uPA: urokinase plasminogen activator; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor. and factors present in its microenvironment [94]. According to the current paradigm, M1 macrophages are associated with anti-tumor functions such as phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC) [95]. Their actions include the production of various pro-inflammatory cytokines, mainly IL-18, IL-6, IL-23, IL-12, IL-1, and TNF-\(\alpha\), which are responsible for the inflammation induced to fight cancer [93; 96; 97]. As the tumor develops, TAMs polarize towards a phenotype similar to M2, promoting the more invasive features of the cancer [98]. The actions of these macrophages are associated with the production of such cytokines as IL-10, IL-13, and IL-4 and transforming growth factor (TGF-\(\beta\)), which support the suppression of inflammation [1; 96]. Moreover, among M2 macrophages, there are M2a, M2b, M2c, and M2d variants varying in the type of inducer and activation pathway. Therefore, the significant diversity of TAMs creates a challenge to clearly confirm the effects of their actions [99; 100]. So far, several pro-tumor products of TAMs have been characterized; they include the following proangiogenic factors: vascular endothelial growth factor (VEGF), IL-8, angiopoeitin 2 (Ang-2), fibroblast growth factor (FGF), and matrix metalloproteinase 9 (MMP-9); factors involved in the remodeling of the ECM: MMP-9 and MMP-12; growth factors: epidermal growth factor (EGF), FGF, and platelet-derived growth factor (PDGF); the following immunosuppressive factors: arginase (Arg), PD-L1, Fas ligand (FaS), IL-10, and TGF, and the following factors responsible for the recruitment of new cells: CXCL-17, CXCL-22, and CXCL-24. On the other hand, TAMs contribute to anti-tumor effects through the activation of T helper 1 (Th1) cells and natural killer (NK) cells, phagocytosis, and the release of reactive oxygen species (ROS) [88]. In the case of many solid tumors, such as ovarian cancer [101], pancreatic cancer [102], glioblastoma [103], breast cancer [104], and bladder cancer [105], the presence of TAMs is associated with a poor prognosis. In CRC, there are also studies indicating a tumor-promoting influence of macrophages [106; 107; 108]. However, numerous studies, particularly those based on patient samples, also demonstrate their suppressive actions [97; 109; 110].