A Gelatin-Oxidized Dextran Hydrogel for Co-Delivery of γδT Cells and Immunostimulatory Agents Potentiates Local Cancer Immunotherapy.

Abstract

Current αβT cell-based immunotherapies largely relying on the use of autologous T cells not only face limitations such as complex manufacturing processes, long production cycles, and high costs, but are also susceptible to immune escape due to tumor antigen loss or downregulation. In contrast, γδT cells offer a unique "off-the-shelf" advantage owing to their HLA-independent recognition of tumor cells, enabling them to target and eliminate malignancies through multiple mechanisms without the need for patient-specific matching. To address the suppressive tumor microenvironment that often impedes γδT cell functions, this study developed an injectable hydrogel system based on oxidized dextran-gelatin for the localized co-delivery of γδT cells along with activating stimulants-IL-2 and zoledronate. This hydrogel with tunable gelation behavior and excellent biocompatibility facilitates sustained release of its cargo. In this system, IL-2 serves as an essential cytokine for supporting the survival, expansion, and functional maintenance of γδT cells, while zoledronate further promotes the proliferation and activation of γδT cells, thereby enhancing their antitumor immune response. In a subcutaneous human osteosarcoma xenograft model, local delivery of CAR-γδT cells combined with zoledronate and IL-2 via this hydrogel system significantly suppressed tumor progression and extended survival. This study thus presents an immunomodulatory strategy to potentiate γδT cell-based therapy against solid tumors.