This study investigates the role of tumor-derived exosomes in organ-specific metastasis. Exosomes from lung-, liver-, and brain-tropic tumor cells preferentially fuse with resident cells at their predicted metastatic sites, such as lung fibroblasts and epithelial cells, liver Kupffer cells, and brain endothelial cells. The uptake of these exosomes by organ-specific cells prepares the pre-metastatic niche, which is crucial for metastasis. Proteomic analysis revealed distinct integrin expression patterns on exosomes, with α6β4 and α6β1 integrins associated with lung metastasis and αvβ5 with liver metastasis. Targeting these integrins reduced exosome uptake and metastasis. Exosome uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Clinical data suggest that exosomal integrin expression profiles could predict organ-specific metastasis. The findings highlight the importance of exosomal integrins in organ-specific metastasis and provide potential targets for therapeutic interventions.This study investigates the role of tumor-derived exosomes in organ-specific metastasis. Exosomes from lung-, liver-, and brain-tropic tumor cells preferentially fuse with resident cells at their predicted metastatic sites, such as lung fibroblasts and epithelial cells, liver Kupffer cells, and brain endothelial cells. The uptake of these exosomes by organ-specific cells prepares the pre-metastatic niche, which is crucial for metastasis. Proteomic analysis revealed distinct integrin expression patterns on exosomes, with α6β4 and α6β1 integrins associated with lung metastasis and αvβ5 with liver metastasis. Targeting these integrins reduced exosome uptake and metastasis. Exosome uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Clinical data suggest that exosomal integrin expression profiles could predict organ-specific metastasis. The findings highlight the importance of exosomal integrins in organ-specific metastasis and provide potential targets for therapeutic interventions.