Genetically Programmable Vesicles for Enhancing CAR‐T Therapy against Solid Tumors

Abstract

AbstractChimeric antigen receptor‐T (CAR‐T) cell therapy has shown remarkable success in eradicating hematologic malignancies; however, its efficacy in treating solid tumors has always been limited due to the presence of an immune‐suppressive tumor microenvironment (TME). Here, genetically programmable cellular vesicles expressing high‐affinity anti‐programmed death‐ligand 1 single chain variable fragment (anti‐PD‐L1 scFv) loaded with glutamine antagonist (D@aPD‐L1 NVs) are developed to metabolically dismantle the immunosuppressive TME and enhance the efficiency of anti‐mesothelin CAR‐T cells in orthotopic lung cancer. As anti‐PD‐L1 scFv can specifically bind to the programmed death‐ligand 1 (PD‐L1) on tumor cells, D@aPD‐L1 NVs enable the targeted delivery of glutamine antagonists to the tumor site and address the upregulation of PD‐L1 on tumor cells, which prevents the premature exhaustion of CAR‐T cells. More importantly, D@aPD‐L1 NVs effectively reduce the number of immunosuppressive cells and promote the recruitment of inflammatory cells and the secretion of inflammatory cytokines in tumor tissues. These unique features of D@aPD‐L1 NVs improve the infiltration and effector functions of CAR‐T cells, which ultimately enhance the anti‐tumor ability and long‐term memory immunity of CAR‐T cells. The findings support that D@aPD‐L1 NVs act as a promising drug to strengthen the effectiveness of CAR‐T cells against solid tumors.