Time‐Encoded Ligand Presentation via a Magnetically Actuated Hydrogel Mitigates T Cell Exhaustion

ABSTRACT Adoptive T cell therapy (ACT) requires ex vivo expansion of tumor‐reactive CD8 + T cells, yet prolonged antigenic stimulation frequently induces exhaustion, limiting persistence and therapeutic efficacy. Here, we present a magnetically actuated, extracellular matrix–mimetic hydrogel that enables reversible control of T cell receptor (TCR) stimulation timing. By embedding αCD3ε/αCD28‐functionalized magnetic nanoparticles within a soft hyaluronic acid matrix, external magnetic fields dynamically expose or conceal stimulatory ligands, allowing programmable alternation between activation and rest. Continuous ligand presentation sustains TCR signaling and drives inhibitory receptor expression and functional exhaustion. In contrast, alternating activation–rest cycles periodically attenuate proximal TCR signaling, reduce exhaustion‐associated marker expression, and bias differentiation toward central memory‐like states while preserving cytokine production and recall capacity. T cells expanded under intermittent stimulation exhibit enhanced antigen‐specific cytotoxicity, reduced dependence on PD‐1 blockade, and superior tumor control in vivo, together with increased CD8 + T cell abundance across analyzed tissues. These results identify temporal control of mechanochemical signaling as a materials‐encoded regulator of T cell fate and provide a non‐genetic strategy for generating functionally competent T cell products with reduced exhaustion‐associated dysfunction and improved antitumor activity.