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

Abstract 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.