MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and are aberrantly expressed in most cancers. They can be secreted in exosomes and transferred between cells, regulating gene expression in recipient cells. This study shows that tumor-secreted miR-21 and miR-29a bind to Toll-like receptors (TLRs), specifically TLR7 and TLR8, in immune cells, triggering a pro-metastatic inflammatory response. This mechanism involves miRNAs acting as paracrine agonists of TLRs, influencing the tumor microenvironment and promoting tumor growth and metastasis. The study identifies that miR-21 and miR-29a can bind to TLR8 in macrophages at the tumor interface, leading to NF-κB activation and secretion of pro-inflammatory cytokines such as TNF-α and IL-6. These findings suggest that miRNAs secreted by cancer cells can activate TLRs in immune cells, contributing to tumor progression. The study also demonstrates that miR-21 and miR-29a can induce TLR7 activation in mice, leading to increased lung metastases. The results highlight the role of miRNAs in tumor-immune system communication and their potential as therapeutic targets for cancer treatment.MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and are aberrantly expressed in most cancers. They can be secreted in exosomes and transferred between cells, regulating gene expression in recipient cells. This study shows that tumor-secreted miR-21 and miR-29a bind to Toll-like receptors (TLRs), specifically TLR7 and TLR8, in immune cells, triggering a pro-metastatic inflammatory response. This mechanism involves miRNAs acting as paracrine agonists of TLRs, influencing the tumor microenvironment and promoting tumor growth and metastasis. The study identifies that miR-21 and miR-29a can bind to TLR8 in macrophages at the tumor interface, leading to NF-κB activation and secretion of pro-inflammatory cytokines such as TNF-α and IL-6. These findings suggest that miRNAs secreted by cancer cells can activate TLRs in immune cells, contributing to tumor progression. The study also demonstrates that miR-21 and miR-29a can induce TLR7 activation in mice, leading to increased lung metastases. The results highlight the role of miRNAs in tumor-immune system communication and their potential as therapeutic targets for cancer treatment.