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Hepatocellular carcinoma (HCC) commonly emerges in an immunologically "cold" state, thereafter protects it away from cytolytic attack by tumor‐infiltrating lymphocytes, resulting in poor response to immunotherapy. Herein, an acidic/photo‐sensitive dendritic cell (DCs)‐based neoantigen nano‐vaccine has been explored to convert tumor immune "cold" state into "hot", and remodel tumor‐associated neutrophils to potentiate anticancer immune response for enhancing immunotherapy efficiency. The nano‐vaccine is constructed by SiPCCl2‐hybridized mesoporous silica with coordination of Fe(III)‐captopril, and coating with exfoliated membrane of matured DCs by H22‐specific neoantigen stimulation. The nano‐vaccines actively target H22 tumors and induce immunological cell death to boost tumor‐associated antigen release by the generation of excess 1O2 through photodynamic therapy, which act as in situ tumor vaccination to strengthen antitumor T‐cell response against primary H22 tumor growth. Interestingly, the nano‐vaccines are also home to lymph nodes to directly induce the activation and proliferation of neoantigen‐specific T cells to suppress the primary/distal tumor growth. Moreover, the acidic‐triggered captopril release in tumor microenvironment can polarize the protumoral N2 phenotype neutrophils to antitumor N1 phenotype for improving the immune effects to achieve complete tumor regression (83%) in H22‐bearing mice and prolong the survival time. This work provides an alternative approach for developing novel HCC immunotherapy strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]