Integrin-ligand interaction mediates the adhesion and migration of many metazoan cells . Here, we report a unique mode of cell migration elicited by the lability of integrin ligands . We found that stationary cells spontaneously turn migratory on substrates where integrin ligands are subject to depletion by cellular force . Using TGT, a rupturable molecular linker, we quantitatively tuned the rate of ligand rupture by cellular force and tested platelets (anucleate cells), CHO-K1 cells (nucleated cells), and other cell types on TGT surfaces . These originally stationary cells readily turn motile on the uniform TGT surface, and their motility is correlated with the ligand depletion rate caused by cells . We named this new migration mode ligand-depleting (LD) migration . Through both experiments and simulations, we revealed the biophysical mechanism of LD migration . We found that the cells create and maintain a gradient of ligand surface density underneath the cell body by constantly rupturing local ligands, and the gradient in turn drives and guides cell migration . This is reminiscent of the phenomenon that some liquid droplets or solid beads can spontaneously move on homogeneous surfaces by chemically forming and maintaining a local gradient of surface energy . Here, we showed that cells, as living systems, can harness a similar mechanism to migrate . LD migration is beneficial for cells to maintain adhesion on ligand-labile surfaces, and might also play a role in the migration of cancer cells, immune cells, and platelets that deplete adhesive ligands of the matrix.