Migrasomes represent an emerging category of extracellular vesicles, but their contribution to metastasis in colorectal cancer (CRC) is not well elucidated. The present research sought to examine the role of migrasomes originating from CRC cells, especially in low-oxygen environments, in driving spread to the liver and altering the immune landscape within tumors.The presence of migrasomes in CRC samples and cell lines was assessed through transmission electron microscopy and immunofluorescence techniques. Functional effects and cell-to-cell interactions were investigated using a murine model of liver metastasis along with single-cell RNA sequencing (scRNA-seq).Migrasome formations were detected in both original CRC tumors and liver metastatic sites. Real-time imaging of living cells showed that CRC cells in hypoxia produced higher quantities of migrasomes. In animal studies, migrasomes from hypoxic conditions accumulated in the liver and accelerated metastatic development there. Analysis via scRNA-seq on liver metastatic lesions indicated that these migrasomes reshaped the tumor ecosystem, particularly by increasing a population of Tmem45a⁺ fibroblasts displaying myofibroblast characteristics and fostering the development of CD5L⁺ macrophages with enhanced ability to engulf dying cells. At the molecular level, NRP2, which is abundant in migrasomes from hypoxic CRC cells, was delivered to macrophages, where it interacted with PROX1 to stimulate CD5L production and enhance receptors involved in efferocytosis. Reducing NRP2 expression in CRC cells prevented the migrasome-driven shift toward CD5L⁺ macrophages and reduced the removal of apoptotic cancer cells.This work illustrates how migrasomes released by hypoxic CRC cells support liver spread by modifying stromal and immune elements, mainly via NRP2/PROX1-directed reprogramming of macrophages into a CD5L⁺ state that favors efferocytosis. The results uncover a novel pathway of cell-to-cell signaling through migrasomes during CRC advancement and suggest a promising target for treating metastatic cases.
