The pre-metastatic niche: mechanisms, heterogeneity, and therapeutic opportunities

Metastasis remains the leading cause of cancer-related mortality. The concept of the pre-metastatic niche (PMN) has provided a new framework for understanding how tumors establish favorable conditions in distant organs before metastatic colonization. This review delineates the cellular and molecular hallmarks of PMN, including immune suppression, vascular/lymphatic remodeling, metabolic reprogramming, and stromal reorganization, and traces their spatiotemporal evolution from initiation to colonization. It further examines the origins of metastatic lesions, with a focus on circulating tumor cells (CTCs) and stromal stem-like cells, highlights the pivotal role of extracellular vesicles (EVs) in mediating intercellular communication, metabolic reprogramming, and therapeutic applications. Deciphering the immune and stromal determinants of PMN formation offers key mechanistic insight into organ-specific metastasis. Consequently, this review explores translational strategies targeting the PMN, such as biomarker development, spatiotemporal profiling aided by artificial intelligence (AI), and immune, metabolic, or EV-based interventions. Deciphering PMN biology is therefore poised to open new avenues for the early interception and treatment of metastasis.