The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, P. R. China.
Adv Sci (Weinh). 2022 Apr;9(11):e2105631. doi: 10.1002/advs.202105631. Epub 2022 Feb 10.
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 SiPCCl -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 O 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.
肝细胞癌 (HCC) 通常出现在免疫“冷”状态,此后它会保护自己免受肿瘤浸润淋巴细胞的细胞溶解攻击,导致对免疫治疗的反应不佳。在此,研究了一种基于酸性/光敏感树突细胞 (DC) 的新型抗原纳米疫苗,以将肿瘤免疫“冷”状态转化为“热”状态,并重塑肿瘤相关中性粒细胞,增强抗癌免疫反应,提高免疫治疗效率。该纳米疫苗由 SiPCCl 杂化介孔硅与 Fe(III)-卡托普利配位而成,并通过 H22 特异性新抗原刺激成熟 DC 的剥落膜进行涂层。纳米疫苗主动靶向 H22 肿瘤,并通过光动力疗法产生过量 O,诱导免疫细胞死亡,从而增强肿瘤相关抗原的释放,作为原位肿瘤疫苗,增强针对原发性 H22 肿瘤生长的抗肿瘤 T 细胞反应。有趣的是,纳米疫苗还存在于淋巴结中,直接诱导新抗原特异性 T 细胞的激活和增殖,抑制原发性/远端肿瘤的生长。此外,肿瘤微环境中酸性触发的卡托普利释放可以将促肿瘤 N2 表型中性粒细胞极化为抗肿瘤 N1 表型,以提高免疫效果,实现 H22 荷瘤小鼠的完全肿瘤消退 (83%) 并延长生存时间。这项工作为开发新型 HCC 免疫治疗策略提供了一种替代方法。
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