Ferroptosis and Pyroptosis Co-Activated Nanomodulator for "Cold" Tumor Immunotherapy and Lung Metastasis Inhibition
Ferroptosis and Pyroptosis Co-Activated Nanomodulator for "Cold" Tumor Immunotherapy and Lung Metastasis Inhibition
复制标题
铁、热下垂共激活的纳米调控剂用于冷肿瘤免疫治疗和抑制肺转移
DOI：
10.1002/adfm.202211698
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发表时间：
2023-05-26
影响因子：
19
通讯作者：
Zhang, Peng
中科院分区：
文献类型：
--
作者：
Jiang, Cong;Li, Xianglong;Zhang, Peng
免疫检查点阻断（ICB）疗法是癌症免疫疗法的新兴策略;然而，ICB疗法的实际效果受到免疫抑制性肿瘤微环境（TME，即，“冷”肿瘤）。尽管工程纳米材料在癌症治疗中对调节TME显示出显著的重要性，但它们中的大多数集中在“免疫沉默”的凋亡过程，其不能引起用于进一步免疫治疗的足够的免疫应答。在本文中，报道了GSH响应性纳米调节剂，其可以通过同时诱导铁凋亡和焦凋亡来逆转用于“冷”肿瘤免疫疗法和肺转移抑制的免疫抑制性TME。纳米调节剂通过将FDA批准的柳氮磺胺吡啶（SAS）和多柔比星（DOX）装载在二硫化物掺杂的有机硅混合胶束上来构建，其中SAS和DOX通过GSH刺激的胶束破裂释放以分别诱导铁凋亡和焦凋亡，通过大量肿瘤相关抗原释放促进树突状细胞（DC）成熟和细胞毒性T淋巴细胞（CTL）升高。体内实验结果证实，在低浓度下实现了纳米调节剂的期望的肿瘤破坏。更重要的是，这种纳米调节剂和程序性死亡配体-1抗体的组合由于升高的成熟DC和CTL而显著抑制原发性肿瘤和远端肺转移。这种通过纳米调节剂诱导的非凋亡性死亡来调节免疫抑制性TME的策略为ICB治疗提供了新的有希望的范例。
Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., "cold" tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on "immunosilent" apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for "cold" tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.