T cells and natural killer (NK) cells are polarized during migration and elimination of target cells. We will investigate how their capability to eliminate tumor cells (including intracellular killing machineries, migration and searching strategies) is regulated by extracellular factors under a physiologically relevant three-dimensional condition, with a special focus on a three-dimensional collagen matrix with different mechanical properties and dynamic structures, collective behavior, and the respective molecular mechanisms. The outcomes can inspire new strategies to optimize functional biomaterials and therapeutic approaches for the treatment of patients.