Mitochondrial transfer: a new perspective on tumor-microenvironment crosstalk driving metastasis

Tumor metastasis is the leading cause of cancer-related deaths. It depends not only on the intrinsic properties of cancer cells but also on their active shaping of the tumor microenvironment. Recent studies have identified mitochondrial transfer(MT) as a key mechanism underlying this tumor-microenvironment crosstalk. Beyond serving as a simple metabolic rescue pathway, MT functions as an intercellular reprogramming process that promotes metastatic progression. In this Review, we propose that MT acts as a tripartite educator during metastasis by driving three coordinated programs: metabolic licensing, immune rewiring, and stromal remodeling. Metabolic licensing enhances the survival and invasive capacity of cancer cells. Immune rewiring helps tumor cells evade immune surveillance. Stromal remodeling reprograms the tumor microenvironment into a permissive niche that supports tumor establishment. We summarize current evidence supporting each of these three programs and discuss emerging therapeutic strategies aimed at either blocking pathological MT or exploiting it for antitumor intervention.