Colorectal cancer cell‐derived extracellular vesicles trigger macrophage production of <scp>IL6</scp> through activating <scp>STING</scp> signaling to drive metastasis

Emerging evidence shows that extracellular vesicles (EVs)-mediated cargo shuttling between different kinds of cells constantly occurs in the tumor microenvironment, leading to the progression of a variety of cancers, but the biological role of DNA enriched in EVs has not been fully elucidated. Here, nuclear chromatin-originated DNA fragments were identified in human serum-derived EVs and exhibited a mild increase in the colorectal cancer patient group, unveiling their potential as a biomarker for cancer diagnosis. Molecular experiments showed that chromatin and mitochondrial DNA fragments adhered to the outer membrane of EVs were released from colorectal cancer cells and transported into macrophages where they stimulated STING signaling cascades, resulting in enhanced STAT1 phosphorylation and IL6 production. Further experiments revealed that STAT1 functioned as a potential IL6 transcription regulator through directly locating at its promoter regions to facilitate IL6 expression in macrophages. In the tumor microenvironment, the accumulated IL6 released by macrophages, in turn, provoked colorectal cancer cell epithelial to mesenchymal transition (EMT) through activating IL6R/STAT3 signaling. Our findings highlighted the importance of DNA carried by EVs in shaping the tumor environment and revealed their potential as a clinical diagnostic biomarker for colorectal cancer.