Trogocytosis has emerged as a key limitation of CAR-based immunotherapy, driving antigen loss, CAR downregulation, and progressive functional impairment of engineered immune cells. This challenge is particularly critical in solid tumors, where sustained antigen engagement and repeated immune synapse formation are required for effective tumor control. Despite its significance, strategies that directly target the biophysical regulation of immune synapse dynamics remain limited.

Here, we engineered CAR-NK cells incorporating a CXCR2-derived VASP-binding motif (Vbm) designed to modulate cytoskeletal organization and immune synapse interactions. We hypothesized that Vbm-mediated actin remodeling could reduce excessive synapse stabilization during repeated target engagement, thereby mitigating trogocytosis-associated dysfunction.

Functionally, Vbm-engineered CAR-NK cells exhibited comparable short-term cytotoxicity but demonstrated enhanced activity under prolonged stimulation conditions. These results suggest that Vbm preserves immediate cytotoxic function while mitigating long-term functional decline through the optimization of immune synapse dynamics.

Collectively, our findings establish cytoskeletal modulation via Vbm as a novel strategy to improve the functional durability of CAR-engineered immune cells and highlight its potential to overcome key barriers in solid tumor immunotherapy.