Zhang, Q.; Roy, S. R.; Zhao, T.; Hou, W.; Xu, C.; Yu, J.; Wu, K.; Hu, X.; Zhang, Y.

The nanoscale organization of cell-adhesive ligands is increasingly recognized as a determinant of cell behavior, yet whether it directly regulates cellular metabolism remains unclear. Here we show that supramolecular clustering of integrin-binding ligands regulates mitochondrial respiratory capacity through integrin-mediated mechanotransduction. Supramolecular ligand clustering induces integrin redistribution and cytoskeletal remodeling, leading to mitochondrial reorganization and a selective constraint on oxidative phosphorylation. This respiratory limitation functionally constrains tumor cell migration and invasion and cannot be overcome by restoring cytoskeletal contractility, whereas replenishing mitochondrial metabolic substrates effectively rescues motility. In a HeLa xenograft model, the integrin-binding supramolecular system suppresses tumor growth and reduces extracellular matrix deposition. These findings identify mitochondrial respiratory capacity as a critical downstream effector of integrin mechanosignaling and establish extracellular ligand organization as a previously unrecognized driver of mechanically encoded metabolic regulation.