The study investigates the compensation mechanisms in tumor cell migration when pericellular proteolysis is blocked. Using HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells in three-dimensional collagen matrices, the authors found that these cells exhibit a constitutive mesenchymal-type movement characterized by β1 integrin and MT1-MMP clustering at fiber binding sites, leading to tube-like proteolytic degradation tracks. Near-complete inhibition of MMPs, serine proteases, and cathepsins induced a conversion to a spherical morphology while maintaining near-undiminished migration rates. This protease-independent migration resulted from a flexible amoeba-like shape change, including propulsive squeezing through preexisting matrix gaps and formation of constriction rings, accompanied by the loss of clustered β1 integrins and MT1-MMP from fiber binding sites and a diffuse cortical distribution of actin. The transition from proteolytic mesenchymal to nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and represents a potential escape strategy in tumor cell dissemination after the abrogation of pericellular proteolysis. The findings were further confirmed in vivo using intravital multiphoton microscopy in the mouse dermis.The study investigates the compensation mechanisms in tumor cell migration when pericellular proteolysis is blocked. Using HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells in three-dimensional collagen matrices, the authors found that these cells exhibit a constitutive mesenchymal-type movement characterized by β1 integrin and MT1-MMP clustering at fiber binding sites, leading to tube-like proteolytic degradation tracks. Near-complete inhibition of MMPs, serine proteases, and cathepsins induced a conversion to a spherical morphology while maintaining near-undiminished migration rates. This protease-independent migration resulted from a flexible amoeba-like shape change, including propulsive squeezing through preexisting matrix gaps and formation of constriction rings, accompanied by the loss of clustered β1 integrins and MT1-MMP from fiber binding sites and a diffuse cortical distribution of actin. The transition from proteolytic mesenchymal to nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and represents a potential escape strategy in tumor cell dissemination after the abrogation of pericellular proteolysis. The findings were further confirmed in vivo using intravital multiphoton microscopy in the mouse dermis.