Abstract Interactions within the tumor microenvironment (TME) are complex and multidirectional, involving immune cells, fibroblasts, extracellular matrix components, exosomes, and numerous soluble mediators. Although the CRC microenvironment is challenging to study, it plays a key role in tumor progression and therapeutic response. Tumor-associated macrophages (TAMs) are particularly difficult to define, as they can shift between M1-and M2-like phenotypes depending on tumor context. Here, we used a direct co-culture of metastatic CRC cells with monocytes to assess how contact-dependent interactions affect the overall condition of the co-culture and monocyte activation. Cellular metabolic activity and viability were assessed, along with macrophage marker expression to determine the dominant phenotype (M1 or M2) in advanced CRC conditions. Additionally, levels of apoptosis and necrosis were evaluated, together with the expression of proteins involved in migration and angiogenesis. Our results demonstrate that direct co-culture represents a promising model for investigating tumor biology in the context of immune cell interactions and enables observation of key mechanisms underlying intercellular communication. Flow cytometric analysis revealed a significant increase in CD163 (67%) and CD206 (65%), suggesting the activation of M2-like features upon contact with advanced CRC. Furthermore, cancer cells cultured alone showed a greater tendency toward necrosis compared with co-culture conditions, indicating an association between the presence of immune cells and reduced tumor cell death. These findings highlight the strong modulation of the microenvironment by metastatic CRC and emphasize the importance of in vitro co-culture models as essential tools for studying tumor biology and intercellular communication mechanisms.