锌铁双金属过氧化物可调节肿瘤基质微环境并增强细胞免疫原性,从而提高乳腺癌免疫疗法的治疗效果。

IF 2.9 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY ACS Earth and Space Chemistry Pub Date : 2024-04-01 DOI:10.1021/acsnano.3c12615
Yujie Lu, Youdong Chen, Guanghui Hou*, Huali Lei, Lin Liu, Xuan Huang, Shumin Sun, Luyao Liu, Xiyu Liu, Jintong Na, Yongxiang Zhao, Liang Cheng* and Liping Zhong*, 
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摘要

免疫疗法已成为治疗乳腺癌的一种潜在方法。然而,乳腺肿瘤僵硬的基质微环境和低免疫原性大大降低了对免疫疗法的敏感性。为了使患者对乳腺癌免疫疗法敏感,研究人员合成了透明质酸修饰的过氧化锌-铁纳米复合材料(Fe-ZnO2@HA,简称FZOH),以重塑基质微环境并增加肿瘤免疫原性。构建的FZOH能自发产生高度氧化的羟基自由基(-OH),降解肿瘤细胞外基质(ECM)中的透明质酸(HA),从而重塑肿瘤基质微环境,增强血液灌注、药物渗透和免疫细胞浸润。此外,FZOH不仅能通过激活caspase-1/GSDMD依赖性途径引发热凋亡,还能通过各种机制诱导铁凋亡,包括增加细胞内铁池中的Fe2+水平、下调FPN1的表达以抑制铁外流,以及激活p53信号通路以导致SLC7A11-GSH-GPX4信号轴失效。用 FZOH 处理 4T1 癌细胞后,它们会发生铁跃迁和热跃迁,并表现出强烈的免疫原性反应。FZOH诱导的肿瘤基质微环境重塑和细胞免疫原性反应共同弥补了癌症免疫治疗的局限性,并显著增强了免疫检查点抑制剂αPD-1的抗肿瘤免疫反应。这项研究为加强乳腺癌的免疫疗法提出了一个视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Zinc–Iron Bimetallic Peroxides Modulate the Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Enhanced Breast Cancer Immunotherapy Therapy

Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide–iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.

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来源期刊
ACS Earth and Space Chemistry
ACS Earth and Space Chemistry Earth and Planetary Sciences-Geochemistry and Petrology
CiteScore
5.30
自引率
11.80%
发文量
249
期刊介绍: The scope of ACS Earth and Space Chemistry includes the application of analytical, experimental and theoretical chemistry to investigate research questions relevant to the Earth and Space. The journal encompasses the highly interdisciplinary nature of research in this area, while emphasizing chemistry and chemical research tools as the unifying theme. The journal publishes broadly in the domains of high- and low-temperature geochemistry, atmospheric chemistry, marine chemistry, planetary chemistry, astrochemistry, and analytical geochemistry. ACS Earth and Space Chemistry publishes Articles, Letters, Reviews, and Features to provide flexible formats to readily communicate all aspects of research in these fields.
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