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首页> 外文期刊>Advanced Functional Materials >Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy
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Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

机译：腺苷抑制引发糊酶和增强癌免疫疗法的启发性表观遗传调制协同作用

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摘要

Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T-cell responses remains challenging. Increasing evidence has indicated that epigenetic alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator gamma-oryzanol (Orz), the adenosine inhibitor alpha, beta-methylene adenosine 5 ' diphosphate (AMPCP), and GSH-activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase-1 into active caspase-1 by increasing ATP levels. Active caspase-1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death-ligand 1 (PD-L1) expression and sensitize tumors to anti-PD-L1 therapy. Thus, the AOZNs nano-formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD-L1 responsive rate and prolonging survival of the B16F10 melanoma-bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy.
机译：克服固体肿瘤中的固体或自适应抗性耐药性，具有有限的T细胞应答仍然具有挑战性。增加的证据表明，表观遗传改变，特别是DNA甲基转移酶和免疫抑制腺苷的过表达是T细胞活化的主要障碍。这里，由表观遗传调节剂γ-甲醇（ORZ），腺苷抑制剂α，β-亚甲基腺苷5'二磷酸（AMPCP）和GSH可激活交联剂组成的肿瘤微环境（TME）的前药纳米摩尔（Aozn）是合成的设计。高谷胱甘肽氧化还原触发ORZ和AMPCP在TME中释放。释放的ORZ作为DNA甲基转移酶抑制剂，通过增加ATP水平将汽笛D（GSDMD）表达和AMPCP转化为活性胱天悬浮酶-1。活性Caspase-1引发了GSDMD裂解和肿瘤细胞诱导的γ凋亡。此外，证明ORZ和AMPCP可能对抗免疫抑制TME具有协同作用。此外，ORZ增强了编程的死亡配体1（PD-L1）表达并使肿瘤敏化以抗PD-L1疗法。因此，Aozns纳米制剂大大改善了orz的疏水性质，其具有安全，实惠，容易获得的优点，以及回归肿瘤生长的效率，增强了B16F10黑色素瘤的小鼠模型的PD-L1响应速率和延长存活。结果，Aozns提供了提高癌症免疫疗法的有希望的策略。

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  • 来源
    《Advanced Functional Materials》 |2021年第20期|2100007.1-2100007.16|共16页
  • 作者

    Xiong Honggang; Ma Xianbin; Wang Xiaolong; Su Wen; Wu Lei; Zhang Tian; Xu Zhigang; Sun Zhi-Jun;

  • 作者单位

    Wuhan Univ Sch & Hosp Stomatol Minist Educ State Key Lab Breeding Base Basic Sci Stomatol Hu Wuhan 430079 Peoples R China|Wuhan Univ Sch & Hosp Stomatol Minist Educ Key Lab Oral Biomed Wuhan 430079 Peoples R China;

    Southwest Univ Sch Mat & Energy Chongqing 400715 Peoples R China|Southwest Univ Chongqing Engn Res Ctr Micronano Biomed Mat & Dev Chongqing 400715 Peoples R China;

    Wuhan Univ Sch & Hosp Stomatol Minist Educ State Key Lab Breeding Base Basic Sci Stomatol Hu Wuhan 430079 Peoples R China|Wuhan Univ Sch & Hosp Stomatol Minist Educ Key Lab Oral Biomed Wuhan 430079 Peoples R China;

    Wuhan Univ Sch & Hosp Stomatol Minist Educ State Key Lab Breeding Base Basic Sci Stomatol Hu Wuhan 430079 Peoples R China|Wuhan Univ Sch & Hosp Stomatol Minist Educ Key Lab Oral Biomed Wuhan 430079 Peoples R China;

    Wuhan Univ Sch & Hosp Stomatol Minist Educ State Key Lab Breeding Base Basic Sci Stomatol Hu Wuhan 430079 Peoples R China|Wuhan Univ Sch & Hosp Stomatol Minist Educ Key Lab Oral Biomed Wuhan 430079 Peoples R China;

    Southwest Univ Sch Mat & Energy Chongqing 400715 Peoples R China|Southwest Univ Chongqing Engn Res Ctr Micronano Biomed Mat & Dev Chongqing 400715 Peoples R China;

    Southwest Univ Sch Mat & Energy Chongqing 400715 Peoples R China|Southwest Univ Chongqing Engn Res Ctr Micronano Biomed Mat & Dev Chongqing 400715 Peoples R China;

    Wuhan Univ Sch & Hosp Stomatol Minist Educ State Key Lab Breeding Base Basic Sci Stomatol Hu Wuhan 430079 Peoples R China|Wuhan Univ Sch & Hosp Stomatol Minist Educ Key Lab Oral Biomed Wuhan 430079 Peoples R China;

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  • 正文语种 eng
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  • 关键词

    adenosine pathway inhibitors; anti#8208; pd#8208; l1; epigenetic modulators; prodrugs; tumor microenvironments;

    机译：腺苷途径抑制剂;抗＆＃8208;pd＆＃8208;l1;表观遗传调节剂;prodrugs;肿瘤微环境;

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