## 4 Cellular Component of the CRC microenvironment
### Myeloid-Derived Suppressor Cells (MDSCs)  
Myeloid suppressor cells (MDSCs) are a diverse population of immature cells that regulate the immune system [201]. This population includes two main subsets: monocytic cells (monocytes, macrophages, and dendritic cells) and granulocyte cells (neutrophils, eosinophils, basophils, and mast cells). Their presence is characteristic of the cancer microenvironment, as they are strongly activated in pathological conditions by injury, transformed cells, or pathogens. The removal of the threat allows them to return to homeostasis. However, the prolonged impact of inflammatory mediators or chemokines, even at low concentrations, maintains the expansion of MDSCs. This may result in strong immunosuppression of the local immune response because immature cells are much more easily recruited and immunomodulated than pro-tumor cells. On the one hand, the persistent level of MDSCs in a pathological state is an emergency mechanism in situations where the threat is not effectively eliminated. However, in the cancer microenvironment, such an effect may block an effective immune response. MDSCs exhibit suppressive effects, mainly against cytotoxic T lymphocytes, but this has also been extended to immunosuppression against NK cells and B lymphocytes [202, 203]. The suppressive role of MDSCs is mainly attributed to their high ROS and ONOO\({}^{-}\) (peroxynnitrite) production [201], which can block TCR, preventing the activation of T lymphocytes. Additionally, MDSCs are characterized by the activity of arginase-1 (Arg-1) and inducible nitric oxide synthase, whose presence results in a decrease in the level of L-arginine necessary for the proper functioning of T cells [204, 205]. In CRC, the presence of MDSCs has been attributed to advanced stages of the tumor. The action of tumor-associated MDSCs has been defined as blocking the expansion of T lymphocytes. Furthermore, the metabolic profile of these cells has been defined as oxidative, which is associated with the production of reactive oxygen species and nitric oxide [206]. While high concentrations of these particles induce anti-tumor effects (through apoptosis induction), the persistent low level of these mediators generates damage to genetic material, enhancing mutations and the instability of cancer cells. Therefore, the presence of oxidative MDSCs may favor CRC progression [207]. The development of MDSCs in the cancer microenvironment is associated with the chemokine CCL-2 level, which drives the expansion of MDSCs. Studies conducted on samples from CRC patients showed that the level of CCL-2 increased with the cancer stage. Blocking the production of CCL-2 in a mouse model resulted in a reduction of this chemokine and, consequently, a decrease in the infiltration of immunosuppressive MDSCs [204; 208]. MDSCs also mediate the resistance of colorectal cancer to chemotherapy. It has been demonstrated that bacteria, such as _Peptostreptoocccus anaerbius_, typical of the gut flora of CRC patients, recruit MDSCs that can participate in resistance to oxaliplatin treatment. This effect indicates the broad spectrum of pro-tumorigenic activity of MDSCs and their ease of differentiation into cells with a malignancy-promoting phenotype [209]. Autophagy, often described as cellular recycling, is considered a process that promotes the development of less malignant MDSCs. It is induced in hypoxic conditions, which are typical for tumors. Therefore, myeloid suppressor cells present in the hypoxic tumor environment are also exposed to autophagy. The induction of autophagy weakens their immunosuppressive activity. Redirecting MDSCs towards the autophagy pathway could be an effective alternative to immunotherapy [210; 211]. However, no results confirming this effect have been found in the case of colorectal cancer. In the context of therapy targeted at MDSCs, recent studies by [PERSON] et al. report the effective action of metformin, an anti-diabetic drug with anti-tumor properties, which limits undesirable infiltration of MDSCs in CRC [212].