## 4 Cellular Component of the CRC microenvironment
### Tumor-infiltrating Lymphocytes (TILs)  
Tumor-infiltrating lymphocytes (TILs) play one of the main roles in the fight against cancer. They induce apoptosis and express cytotoxic-dependent immune response, thereby limiting the proliferation and migration of abnormal cells [167; 168]. In the cancer microenvironment, there is a mixture of cytotoxic T lymphocytes (Tc, CD8+), helper T cells (Th,CD4+), B lymphocytes, and NK cells classified as cytotoxic cells. The homeostasis between these lymphocyte populations is crucial because, in the tumor microenvironment, effector T lymphocytes are assigned an anti-tumor role, while some helper cells (e.g., Th17) have partially immunosuppressive functions. Therefore, disruption of this balance may result in tumor progression [169; 170; 171]. After antigen recognition in the induction phase, cytotoxic lymphocytes and NK enter the effector phase, which is the actual stage of fighting cancer and involves the release of cytolytic granules containing granzymes, perforin, cytotoxic cytokines (IL-2, IL-12, IFN-\(\gamma\)), TNF-\(\alpha\), and FasL [170; 172]. Studies have confirmed that high infiltration of CD8+ lymphocytes correlates with the longer survival of patients, including those with colorectal cancer. Histopathological analyses of CRC suggest that the infiltration of TILs into the tumor area has a protective effect on patients, especially those with microsatellite instability (MSI) tumors. This also indicates the dependence of the effectiveness of the immune system on the genetic background of cancer [165; 168]. NK cells are characterized by a high diversity and a wide range of surface markers. Generally, they are considered similar to effector lymphocytes, but they exhibit greater cytotoxicity and faster reaction times, especially towards tumors [170]. Their presence in the microenvironment of colorectal cancer is associated with higher patient survival rates [173]. This may be due to the fact that, as producers of IFN-\(\gamma\), NK cells regulate the function of cytotoxic lymphocytes, mainly by participating in the maturation of dendritic cells, supporting the immune reaction, and driving a direct cytotoxic reaction against cancer cells [174]. Moreover, the main mechanism of the NK fight against transformed cells is antibody-dependent cellular cytotoxicity. This property has been used in studies on the treatment of CRC using NK cells and radiotherapy combined with cetuximab. NK cells irradiated or combined with antibodies have been shown to effectively fight cancer. Additionally, their high infiltration increased the likelihood of the effective action of modified NK cells in the treatment of CRC [175]. The population of Th cells includes a wide range of those classified into subtypes based on the factors they produce: Th1, Th2, Th17, and follicular helper T cells (TFH). Th lymphocytes are mainly responsible for the elimination of cancer cells by activating the immune system during an immune response. However, the action of this lymphocyte group shows some inconsistency due to their diversity. Th1 cells, expressing IFN-\(\gamma\) and TNF-\(\alpha\), are attributed to anti-tumor activity in colorectal cancer, while other subpopulations show varied effects depending on the type and stage of the tumor. Some subsets of CD4+ T cells also have the potential for direct fighting against tumors through the acquisition of cytotoxic abilities. Such abilities have been observed in in vivo models [170; 174; 176; 177; 178; 179]. Th17 lymphocytes, expressing IL-17, have been classified as predictors of poor prognosis not only in CRC [180; 181] but also in ovarian cancer [182]. The negative impact of IL-17 is associated with IL-6 derived from cancer cells, whose production in the tumor microenvironment increases under the influence of IL-17, promoting tumor growth and the polarization of subsequent Th17 lymphocytes. Therefore, Th17 lymphocytes in CRC are mainly considered pro-tumorigenic [174; 183].