Stiffness-related mitochondria transfer promotes tumor progression through metabolic reprogramming

The physical properties of the tumor microenvironment (TME), particularly extracellular matrix stiffness, are key factors influencing cancer progression. While intercellular mitochondrial transfer is emerging as a vital mechanism for tumor metabolic adaptation, its potential interaction with TME mechanical properties remains unexplored. Overall design: Here, we demonstrated that matrix stiffness is a crucial negative regulator of mitochondrial transfer from macrophages to tumor cells. Increased mitochondrial uptake by tumor cells compensates for functional limitations in soft niches, thereby promoting metabolic reprogramming to drive proliferation and invasion. Furthermore, downregulating TIAM1 via the DDR2-FAK-TIAM1 signaling axis activates RhoA, enhancing mitochondrial endocytosis and leading to improved energy metabolism. Altogether, this study unveiled a novel mechano-metabolic coupling where physical cues influence organelle-based interplay, revealing a distinct adaptive strategy for tumor cells in soft TME niches and offering new therapeutic targets.