Cytosolic Delivery of Thiolated Neoantigen Nano-Vaccine Combined with Immune Checkpoint Blockade to Boost Anti-Cancer T Cell Immunity.

Although tumor-specific neoantigen-based cancer vaccines hold tremendous potential, it still faces low cross-presentation associated with severe degradation via endocytosis pathway. Herein, a thiolated nano-vaccine allowing direct cytosolic delivery of neoantigen and Toll like receptor 9 agonist CpG-ODN is developed. This approach is capable of bypassing the endo-/lysosome degradation, increasing uptake and local concentration of neoantigen and CpG-ODN to activate antigen-presenting cells, significantly strengthening the anti-cancer T-cell immunity. In vivo immunization with thiolated nano-vaccine enhanced the lymph organ homing and promoted the antigen presentation on dendritic cells, effectively inhibited tumor growth, and significantly prolonged the survival of H22-bearing mice. Strikingly, further combination of the thiolated nano-vaccine with anti-programmed cell death protein-1 antibody (αPD-1) could efficiently reverse immunosuppression and enhance response rate of tumors, which led to enhanced tumor elimination, complete prevention of tumor re-challenge, and long-term survival above 150 d. Collectively, a versatile methodology to design cancer vaccines for strengthening anti-cancer T-cell immunity in solid tumors is presented, which could be further remarkably enhanced by combining with immune checkpoint inhibitors.