Extracellular vesicles in colorectal cancer: M2 polarization, bidirectional regulation of CAFs, metastasis, and treatment

Extracellular vesicles (EVs), as key mediators of intercellular communication, play a critical regulatory role in the pathogenesis and treatment of colorectal cancer (CRC). By carrying diverse bioactive molecules-including miRNAs, lncRNAs, circRNAs, and DNA-EVs influence multiple components of the tumor microenvironment (TME), such as promoting macrophage M2 polarization, reducing T and B Cell activity and proliferation, enabling evasion of natural killer (NK) cell surveillance, and regulating bidirectional fibroblast interactions in CRC. Furthermore, CRC-derived EVs can promote CRC metastasis by stimulating angiogenesis in endothelial cells, facilitating epithelial-mesenchymal transition (EMT), and promoting the formation of pre-metastatic niches. Through an analysis of the role of EVs in the pathogenesis of CRC, numerous studies have found that EVs can augment the efficacy of immunotherapy. At the same time, both mesenchymal stem cell-derived EVs and engineered EVs (such as plant-derived and microorganism-derived EVs) can play significant roles in the treatment of CRC. However, most current research remains in the in vitro and in vivo trial stages. Due to difficulties in purification and engineering, as well as inherent heterogeneity, clinical translation remains challenging; consequently, no related products have yet been brought to market. Most clinical studies remain focused on diagnostic applications, while trials for therapeutic applications are still recruiting participants. Against this backdrop, we highlight the limitations and challenges in EVs research, with the aim of providing better research directions for the clinical translation of CRC treatments.