3D hydrogel platform with macromolecular actuators for precisely controlled mechanical forces on cancer cell migration.

Mechanical forces play a critical role in regulating cancer cell behavior, particularly during metastasis. Here we present a three-dimensional hydrogel platform embedded with near-infrared-responsive macromolecular actuators that enable precise mechanical stimulation of specific integrin subtypes in cancer cells. By leveraging this system, we investigate how different force parameters-magnitude, frequency, and duration-affect the migration and invasion of ovarian cancer cell spheroids, focusing on the integrins αvβ3 and αvβ6. We find that mechanical stimulation enhances collective invasion at early stages and triggers a mesenchymal-to-amoeboid transition during later migration, especially when high-frequency, large-amplitude forces disrupt αvβ3-ligand interactions. In contrast, cells engaging αvβ6-through higher-affinity binding-show limited transition under similar conditions. Molecular simulations support these findings by revealing the underlying mechanics of integrin-specific responses. This 3D hydrogel platform provides a powerful tool for studying mechanotransduction in cancer cells and offers potential insights for developing targeted cancer therapies.