Exosomes promote pre-metastatic niche formation in lung cancer

Lung cancer is a major cause of cancer-related mortality worldwide. Distant metastasis is the primary driver of poor prognosis, and the formation of the pre-metastatic niche (PMN) represents a critical early event in this process. Tumor cells remodel the microenvironment of distant organs by releasing various factors, including exosomes, which create a favorable environment for the colonization and growth of circulating tumor cells (CTCs). Exosomes carry diverse molecular cargos including proteins, RNAs, and lipids, and they play a pivotal role in PMN formation. They modulate several microenvironmental components, including immune cells, endothelial cells, and fibroblasts, by promoting immune evasion, angiogenesis, and extracellular matrix remodeling, thereby enhancing the metastatic potential of cancer cells. This review systematically discusses how distinct lung cancer-derived exosomes (LCDEs) subpopulations contribute to PMN formation, emphasizing how the heterogeneous molecular cargos they carry facilitate metastasis through immune suppression, angiogenesis, and matrix remodeling. It also highlights efforts to understand the cellular origins of LCDEs and how this influences their functional specificity. Unlike existing reviews, we establish the first functional classification system for LCDEs based on their niche-modulating actions, and rigorously evaluate their clinical potential as both biomarkers and therapeutic vehicles. We further provide a critical appraisal of technical limitations in exosome-based applications. These insights advance the translational development of LCDE-targeted strategies.