## 3 Indirect Communication in the Tumor Microenvironment
### Soluble Mediators  
Soluble mediators, such as cytokines, chemokines, and signaling molecules, similar to EVs, facilitate multifaceted communication in the CRC microenvironment [51]. Depending on their composition and proportions, their actions in the TME may induce both pro- and anti-tumor effects [52]. By controlling biological functions in the TME, they influence the differentiation, proliferation, and migration of cells. Therefore, the disruption of the balance between these soluble mediators can be one of the determinants of CRC progression [51; 53]. The tumor microenvironment includes signaling molecules released from both cancer cells and infiltrating tumor-associated cells, making their actions dependent on their origin. The goal of cancer cells is obvious: to autocrinally drive proliferation and recruit new niches to increase tumor mass. However, mediators released by tumor-infiltrating cells are initially an important weapon in the fight against cancer, but their long-term action may have the opposite effect [54; 55]. Among the main pro-inflammatory cytokines in the TME are interleukins (IL), e.g., IL-1\(\beta\), IL-6, and IL-8 (CXCL-8) and tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)) [56]. Increased production of IL-1\(\beta\) is common in many types of cancer (including lung and breast cancer), but it is not fully known which specific niche cells are responsible for its increased production [57; 58; 59]. IL-1\(\beta\) has been attributed to regulating processes such as proliferation, differentiation, and apoptosis of cells. Additionally, it stimulates the production of inflammatory mediators, i.e., TNF-\(\alpha\), IL-6, IL-8, IL-17, cyclooxygenase-2 (COX-2), and (prostaglandin E2) PGE2. However, its role in the CRC requires further research [60]. It is known that IL-1\(\beta\) can promote the mesenchymal phenotype of CRC through EMT and stimulate the self-renewal of colorectal cancer stem cells [61]. Studies on CRC patient samples confirm its increasing levels up to stage III, which then decrease in stage IV. This indicates that its level is dependent on the advancement of cancer (up to stage III) and makes it a prognostic marker until metastasis occurs [62]. Furthermore, the role of IL-1\(\beta\) in some tumor invasions (like breast cancer) is supported by studies where inhibiting its production correlates with a lower likelihood of metastasis and an improvement in the anti-tumor immune response. Its operation in this respect should also be checked in the CRC [63; 64]. In CRC, IL-1\(\beta\) is also associated with chemoresistance [65]. IL-6 is a pleiotropic pro-inflammatory cytokine that also plays a role in promoting cancer. Patients with colorectal cancer show increased levels of IL-6 compared to healthy individuals. This may be due to its production by cancer cells themselves as well as macrophages, CAFs, and T lymphocytes induced by cancer. Its action is associated with the IL-6/STAT3 (signal transducer and activator of transcription 3) pathway, which in CRC is linked to cell proliferation, the inhibition of apoptosis, invasion, metastasis, angiogenesis, and chemotherapy resistance. Additionally, IL-6 activates the proliferation of CAFs, which are also its source, maintaining a pro-tumor microenvironment in cancer and enhancing the metastatic phenotype of CRC [66; 67; 68]. Studies by [PERSON] et al. demonstrated a correlation between the level of IL-6 and the occurrence of metastasis to lymph nodes in CRC [69]. TNF-\(\alpha\), i.e., a promoter of inflammation, is responsible for the initiation and maintenance of the production of many cytokines, participation in leukocyte recruitment, and contribution to angiogenesis. However, these functions make it a factor that promotes tumor development in the tumor microenvironment. TNF-\(\alpha\) is mainly produced by macrophages and monocytes, but also by cancer cells, aiming to escape immune surveillance [70; 71].