Exosome-mediated macrophage reprogramming and immune regulation during colorectal cancer progression

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and continues to be a major cause of cancer-related mortality. CRC progression was earlier thought to be driven by genetic mutations within epithelial cells; however, growing evidences clear that tumor progression is not determined only by the genetic alterations within cancer cells. Importantly, the surrounding tumor microenvironment (TME) plays a crucial role in shaping disease progression and therapeutic response. The TME contains a complex network of stromal cells and immune cells that continuously interact with tumor cells through the release of soluble factors as well as extracellular vesicles. Among the immune cells present within the TME, macrophages are particularly abundant and functionally diverse and can adopt different activation states depending on the signals they receive from their surroundings. The signalling molecule includes soluble cytokines, growth factors, and extracellular vesicles as important mediators of intercellular communication during cancer progression. Among these vesicles, exosomes have received particular attention due to their ability to transfer biologically active molecules from donor to recipient cells and emerge as a key regulator of tumor progression and immunomodulation. The current study was designed to understand the mechanistic role of CRC-derived exosomes in the regulation of macrophage polarization, with a specific focus on NF-κB signalling pathways. In addition, we also explore the therapeutic potential of targeting the immune checkpoint PD-1/PD-L1 axis.