Orchestrating the pre-metastatic niche: roles of stromal mediators and immune cells in metastatic progression and therapeutic targeting.

Tumor metastasis is the leading cause of mortality in patients with malignant cancers, and the establishment of the pre-metastatic niche (PMN) is recognized as a pivotal step in this process. With growing insight into the tumor microenvironment, the roles of immune cells and stromal mediators in PMN formation have gained increasing attention. This review systematically summarizes the core functions of stromal components and immune cells in PMN development and their coordinated regulatory mechanisms within the metastatic cascade, encompassing macrophages, tumor-associated fibroblasts, neutrophils, myeloid-derived suppressor cells, T cells, and other cellular elements. Particular emphasis is placed on extracellular matrix (ECM) remodeling and immune suppression as central determinants of PMN establishment. Furthermore, the Organotropism mechanisms underlying PMN formation are discussed, along with their potential implications for future research and clinical translation. In addition, the dynamic transition from PMN to the metastatic niche (MN) is examined, with a focus on the regulation of tumor cell dormancy and reactivation. Building on these insights, the review further discusses therapeutic strategies targeting stromal mediators and immune cells, along with the potential clinical value of related interventions. Future studies should aim to clarify the molecular mechanisms underlying these complex interactions to provide a theoretical foundation and new directions for cancer prevention and treatment.