佐剂
肿瘤微环境
癌症研究
细胞毒性T细胞
免疫系统
免疫疗法
免疫抑制
免疫原性细胞死亡
癌症免疫疗法
促炎细胞因子
免疫学
免疫增强剂
生物
炎症
生物化学
体外
作者
Lingxiao Zhang,Jing Zhao,Xi Hu,Chenhan Wang,Yingbo Jia,Chaojie Zhu,Shangzhi Xie,Ji‐Young Lee,Fangyuan Li,Daishun Ling
标识
DOI:10.1002/adma.202206915
摘要
Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+ , promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors.
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