Exosomes as architects of cancer metastasis: Molecular conversations driving metastatic fate

Formation of distant tumors from initial primary sites, metastasis, is a principal cause of cancer-related mortality from solid cancers and is associated with poor clinical and surgical outcomes. The development of a pre-metastatic niche precedes organ-specific metastatic colonization and serves as a central determinant of metastatic progression. The evolution of pre-metastatic niche research has expanded our understanding of how primary tumors prime distant organs for metastatic colonization. Progress from descriptive observations to mechanistic insights has clarified the cellular and molecular factors that create permissive secondary microenvironments. These findings have identified critical pathways that regulate pre-metastatic niche formation and support the development of strategies to prevent metastatic progression. A critical element in reprogramming the tumor microenvironment involves exosomes, cell-derived extracellular vesicles (EVs) enriched in proteins, nucleic acids, and lipids. These vesicles mediate intercellular communication and actively remodel local and systemic microenvironments. Exosomes play essential roles in tumor metastasis, a leading cause of cancer-related mortality from advancing solid cancers. Circulating tumor-derived exosomes promote metastatic initiation and progression and contribute to organotropism by directing metastatic spread to specific distant sites. Advances in exosome biology and engineering have enabled the development of novel strategies for therapeutic intervention. In this review, we summarize recent progress in comprehending exosome-mediated regulation of metastasis, with an emphasis on fundamental mechanisms and emerging approaches for therapeutic targeting in advanced cancers.