Role of colorectal cancer-derived exosomes in modulating macrophage phenotype during tumor development

Colorectal cancer (CRC) is one of the deadliest malignancies and is characterized by a complex tumor microenvironment (TME) comprising cancer and immune cells engaged in extensive signaling crosstalk. The composition of the TME changes with disease stage and contributes to tumor aggressiveness and resistance to therapy. Although tumor associated immune cells are known to promote cancer progression, the mechanisms underlying these effects are not fully understood. In this study, we show that communication between CRC cells and immune cells, particularly tumor associated macrophages (TAMs), is mediated by soluble factors and extracellular vesicles, including exosomes. We find that the phenotypic transition of CRC associated TAMs is initially driven by activation of the nuclear factor kappa B transcription factor. With time, exosomal cargo promotes anti-inflammatory signaling, leading to the development of a tumor supportive microenvironment that favors tumor growth. Together, these findings highlight exosome mediated modulation of TAM function as an important mechanism in CRC progression and suggest that targeting this pathway to delay the shift of TAMs from pro-inflammatory to tumor supportive states may attenuate CRC aggressiveness.