Branched actin network supports cell migration through extracellular microenvironments. However, it is unknown how intracellular proteins adapt the elastic properties of the network to the highly varying extracellular resistance. Here we develop a three-dimensional assembling model to simulate the realistic self-assembling process of the network by encompassing intracellular proteins and their dynamic interactions. Combining this multiscale model with finite element method, we reveal that the network can not only sense the variation of extracellular resistance but also self-adapt its elastic properties through remodeling with intracellular proteins. Such resistance-adaptive elastic behaviours are versatile and essential in supporting cell migration through varying extracellular microenvironments. The bending deformation mechanism and anisotropic Poisson’s ratios determine why lamellipodia persistently evolve into sheet-like structures. Our predictions are confirmed by published experiments. The revealed self-adaptive elastic properties of the networks are also applicable to the endocytosis, phagocytosis, vesicle trafficking, intracellular pathogen transport and dendritic spine formation.

Cells migrate by adapting their leading-edge behaviors to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviors emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we establish a spatiotemporal “resistance-adaptive propulsion” theory based on the interactions between Arp2/3 complexes and polymerizing actin filaments and a multiscale dynamic modeling system spanning from molecular proteins to the cell. We quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggers a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers the cell with both powerful and flexible migratory capabilities to deal with complex ECMs but also enables efficient utilization of intracellular proteins by the cell. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodeling. We also show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force–regulated actin filament–Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modeling system at the protein level.