Professor Song Li

Mechano-Immunoengineering for Cancer Therapy

Abstract

Immune cells are highly responsive to mechanical cues within their microenvironment; however, how to harness this mechanosensitivity to improve cell manufacturing and disease therapy remains unresolved. Here, we present a scalable microfluidic platform for fabricating microspheres that act as synthetic viscoelastic activating cells (SynVACs) with programmable mechanical and biochemical properties. We show that the viscoelasticity of SynVACs profoundly influences T cell function. Compared with rigid or purely elastic artificial cells, SynVACs promote superior T cell expansion, characterized by an increased CD8+/CD4+ T cell ratio, enhanced tumor cytotoxicity, greater efficiency in chimeric antigen receptor (CAR) transduction, and a marked enrichment of T memory stem cells. The resulting engineered CAR-T cells exhibit improved tumor clearance not only in a human lymphoma mouse model but also in an ovarian cancer xenograft model, maintaining prolonged in vivo persistence that suppresses tumor growth and recurrence. These findings reveal the critical role of mechanical signaling in T cell engineering and highlight the potential of SynVACs as a powerful tool for CAR-T therapy and immunoengineering. Building on this platform, we further developed a biomimetic "charging station" that integrates chemotactic and activation cues to facilitate the recruitment, activation, and expansion of CAR-iNKT cells. This system significantly enhances tumor infiltration, strengthens long-term immune memory, and achieves superior efficacy compared to conventional CAR-iNKT therapies in solid tumor models.