Nanomessenger-mediated signaling cascade for antitumor immunotherapy
Nanomessenger-mediated signaling cascade for antitumor immunotherapy
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纳米信使介导的信号级联用于抗肿瘤免疫治疗
DOI：
10.1021/acsnano.1c02765
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发表时间：
2021
期刊：
影响因子：
17.1
通讯作者：
Liu You-Nian
中科院分区：
文献类型：
--
作者：
Zhao Henan;Wang Liqiang;Zeng Ke;Li Jianghua;Chen Wansong;Liu You-Nian
化学信使被认为是参与调节各种生理和代谢活动的信号分子。然而，由于生物过程的复杂性，它们通常表现出有限的调节效率。特别是对于肿瘤细胞，抗死亡途径和肿瘤转移容易被激活以抵抗化学信使调节，进一步损害抗肿瘤结果。因此，迫切需要开发利用化学信使根除肿瘤的策略。在此，制备具有信号转导级联的纳米信使，以放大化学信使的调节活性并介导抗肿瘤免疫治疗。Ca2+和H2S作为两种化学信使从纳米基质中释放，以协同提高细胞内Ca2+应激并介导随后的细胞死亡。同时，锌原卟啉（ZnPP）作为信使放大剂抑制肿瘤细胞的抗死亡作用。肿瘤细胞通过Ca2+依赖的细胞死亡信号转导级联反应释放肿瘤相关抗原，进而作为原位瘤苗激活抗肿瘤免疫，在体研究显示原发肿瘤和远处转移瘤均被显著根除。此外，构建免疫记忆以抑制肿瘤转移和复发。这项工作将级联工程引入化学信使，从而提供了一种放大化学信使介导的细胞调节的策略，这将促进化学信使介导的免疫治疗的未来发展。
Chemical messengers have been recognized as signaling molecules involved in regulating various physiological and metabolic activities. Nevertheless, they usually show limited regulatory efficiency due to the complexity of biological processes. Especially for tumor cells, antideath pathways and tumor metastasis are readily activated to resist chemical messenger regulation, further impairing antitumor outcomes. Therefore, it is imperative to develop strategies for tumor eradication with chemical messengers. Herein, a nanomessenger was prepared with signaling transduction cascades to amplify the regulatory activity of chemical messengers and mediate antitumor immunotherapy. Ca2+and H2S as two chemical messengers were released from nanomessengers to synergistically elevate intracellular Ca2+stress and mediate subsequent cell death. Meanwhile, zinc protoporphyrin (ZnPP) as a messenger amplifier suppressed the antideath effect of tumor cells. As a result, tumor cells underwent Ca2+-dependent cell deathviasignaling transduction cascades to release tumor-associated antigens, which further served as anin situtumor vaccine to activate antitumor immunity.In vivostudies revealed that both primary tumors and distant metastases were markedly eradicated. Furthermore, immunological memory was fabricated to arrest tumor metastasis and recurrence. This work introduces cascade engineering into chemical messengers and thus offers a strategy for amplifying chemical messenger-mediated cellular regulation, which would promote the future development of chemical messenger-mediated immunotherapy.̀