Matrix Viscoelasticity Regulates Dendritic Cell Migration and Immune Priming

ABSTRACT The tumor microenvironment shapes immune surveillance through its mechanical properties, yet the role of matrix viscoelasticity remains unclear. Here, we used a tunable collagen system that models human tissue viscoelasticity to define how matrix relaxation directs dendritic cell (DC) behavior. Slow‐relaxing, elastic networks restrict actomyosin‐driven remodeling, limiting DC motility and reducing DC‐T cell encounters and activation. Blocking DC migration in fast‐relaxing matrices recapitulated key aspects of the impaired T cell priming seen in elastic networks, identifying migration as a mechanical checkpoint for immune activation. Prolonged confinement in elastic matrices induced a mechanomemory state, locking DCs into a state of reduced motility and altered chromatin accessibility. Studies using patient‐derived ependymoma samples confirmed these findings, establishing viscoelastic relaxation as a key physical regulator of immune priming. Together, this tunable viscoelastic platform provides a defined, human‐relevant model to dissect and model mechanical control of immunity for therapeutic design.