## 6 Conclusions  
The interactions between cancer and the tumor microenvironment are very complex because they involve a wide spectrum of cells, both normal and cancerous, as well as extracellular elements (Figure 1). This review focused solely on the most important components, such as immune cells, fibroblasts, vascular cells, and the extracellular matrix. However, the TME includes many more cells and factors secreted by these cells, making further research in this direction extremely important, especially as there have been increasing reports in recent decades suggesting that the TME effectively supports cancer development. Moreover, most of the cells in the TME include undifferentiated cells, which makes their recruitment and immunoediting much easier. Therefore, the question arises whether depriving the tumor of its microenvironment would be an effective way to enhance immunotherapy. This seems to be the right direction; however, the complexity of intercellular interactions in the TME complicates targeting its elements.  
So far, in the treatment of CRC, therapies targeting the immunological checkpoints of the microenvironment (PD-1/PD-L1, CTLA-4) and proteins associated with tumor angiogenesis (VEGFR) have been approved. However, the genetic diversity of CRC means that this therapy is effective only in specific subtypes, such as dMMR-MSI-H CRC. In addition to the genetic background, elements of the TME, such as immune cells, fibroblasts, vascular cells, and their products, may mediate resistance to immunotherapy. Therefore, it is necessary to further understand the interactions between tumor microenvironment cells and verify biomarkers to better understand tumor function.  
First of all, efforts should be focused on blocking the infiltration of normal cells, which have been shown in several studies to play a protective role against the tumor. They support further growth and the avoidance of the immune response. Indeed, initial infiltration and induction of inflammation in some cases correlate with patient survival chances, but this process evolves over time and favors the tumor. Therefore, another approach is to try to inhibit the transformation of normal cells into cells with pro-tumor potential. In the case of immune cells, high plasticity may also be an advantage for restoring the normal phenotype of immune cells.  
Developing targeted therapies focused on the TME is becoming a less distant direction in cancer treatment, but it certainly requires a more holistic approach, taking into account all the intercellular networks of this complex system.  
Conceptualization, P.P., M.P. and R.P.; methodology, P.P.; validation, P.P., M.P. and R.P.; formal analysis, P.P., M.P. and R.P.; investigation, P.P.; resources, P.P., M.P. and R.P.; data curation, P.P., M.P. and R.P.; writing--original draft preparation, P.P.; writing--review and editing, P.P., M.P. and R.P.; visualization, M.P. and P.P.; supervision, R.P. and M.P.; project administration, P.P., M.P. and R.P.; funding acquisition, R.P. All authors have read and agreed to the published version of the manuscript.  
This research received no external funding.  
Not applicable.  
The authors confirm that the data supporting this study are available within the article. Data supporting this study are also available from the corresponding author on justified request.  
The authors declare no conflicts of interest.