DON-Loaded Nanodrug-T Cell Conjugates With PD-L1 Blockade for Solid Tumor Therapy.

Adoptive T-cell therapy (ACT) holds significant promise for treating solid tumors but is often constrained by insufficient T-cell infiltration, survival, and functional persistence. To overcome these obstacles, we developed DON-loaded nanodrug-T cell conjugates with PD-L1 blockade, forging a dynamic mutualistic relationship between T cells and therapeutic agents. Sustained release of glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) within these conjugates continuously enhances T-cell endurance and potency by promoting memory differentiation and elevating crucial adhesion and motility genes. Concurrently, PD-L1 blocking peptides liberate T cells from immunosuppression, assisting T cells with precision toward tumor sites. This dual-targeting strategy-T cells directed at tumor antigens and peptides at PD-L1- enriches the tumor microenvironment with potent therapeutics, amplifying T cell-driven tumor destruction. Our approach effectively overcomes the critical barriers of ACT-infiltration, persistence, and efficacy-unlocking the full therapeutic potential of T-cell therapy against complex solid tumors.