Bionic immunoactivator copresenting autophagy promoting and costimulatory molecules for synergistic cancer immunotherapy

Immunotherapy has great promise in improving malignant tumor treatment. However, the efficacy of existing strategies is often limited by the immunosuppressive environment. Here, we demonstrate an in situ bionic immunoactivator, PLT-Bec1/DTA-1, with possessed natural advantages of platelets for tumor recruitment and activation, on which DTA-1 (CD357 monoclonal antibody) and Bec1 were tethered as combined immune boosters. PLT-Bec1/DTA-1, as a self-triggered release repository, can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles (PMPs), thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells (DCs) and T cells via autophagy inducibility, coupled with glucocorticoid-induced tumor necrosis factor receptor (GITR)-triggered T_Reg suppression, remodeled the immunosuppressive network of tumor microenvironment. PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation, and alleviated the low activity state of bone marrow-derived dendritic cells (BMDCs) in tumor suppressive environment. PLT-Bec1/DTA-1 inhibited tumor recurrence (5- and 13-fold lower of control group in tumor volume) and CD8⁺ T/T_Reg ratio (6.3- and 8.8-fold vs. control group) in mouse tumor model after intravenous or subcutaneous administration. Also, PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation, and was slightly superior to the combined of Bec1 and PD-L1. Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers, eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication. All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.