副凋亡诱导剂可有效触发免疫原性细胞死亡，用于 IDO 抑制的转移性肿瘤免疫治疗,ACS Nano

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副凋亡诱导剂可有效触发免疫原性细胞死亡，用于 IDO 抑制的转移性肿瘤免疫治疗
ACS Nano ( IF 15.8 ) Pub Date : 2023-05-18 , DOI: 10.1021/acsnano.2c11964
Rong-Rong Zheng ₁ , Lin-Ping Zhao ₁ , Chu-Yu Huang ₁ , Hong Cheng ₂ , Ni Yang ₁ , Zu-Xiao Chen ₁ , Hua Cai ₁ , Wei Zhang ₁ , Ren-Jiang Kong ₂ , Shi-Ying Li ₁

Affiliation

Paraptosis 的特点是内质网 (ER) 和线粒体的广泛空泡化，这将导致损伤相关分子模式的释放，从而促进免疫原性细胞死亡 (ICD)。然而，肿瘤可以形成免疫抑制微环境以影响 ICD 激活以达到免疫逃逸的目的。在此，构建了一种旁凋亡诱导剂 (CMN)，通过抑制吲哚胺 2,3-双加氧酶 (IDO) 的活性来增强 ICD 效应以实现有效的免疫治疗。最初，CMN 是由铜离子 (Cu ²⁺)、morusin (MR) 和 IDO 抑制剂 (NLG919) 通过非共价相互作用。不需要额外的药物载体，CMN 具有非常高的药物含量，并表现出良好的 GSH 分解响应性。随后，释放的 MR 可触发细胞凋亡，导致 ER 和线粒体广泛空泡化，有助于激活 ICD 进行免疫治疗。此外，NLG919 会抑制 IDO 以重塑肿瘤微环境并促进细胞毒性 T 细胞的活化，从而导致强烈的抗肿瘤免疫。体内含量丰富研究表明，CMN 在抑制原发性肿瘤以及转移性和再攻击性肿瘤的增殖方面具有优势。这种 GSH 反应性细胞凋亡诱导剂可能提供一种有前途的策略来触发 ICD 和增强肿瘤免疫治疗。

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Paraptosis Inducer to Effectively Trigger Immunogenic Cell Death for Metastatic Tumor Immunotherapy with IDO Inhibition

Paraptosis is characterized by the extensive vacuolization of endoplasmic reticulum (ER) and mitochondria, which will cause the release of damage-associated molecular patterns to promote immunogenic cell death (ICD). However, the tumor can develop an immunosuppressive microenvironment to affect the ICD activation for the purpose of immune escape. Herein, a paraptosis inducer (CMN) is constructed to amplify the ICD effect for efficient immunotherapy by inhibiting the activity of indoleamine 2,3-dioxygenase (IDO). Initially, CMN is prepared by the assembly of copper ions (Cu²⁺), morusin (MR), and IDO inhibitor (NLG919) through noncovalent interactions. Without the need for extra drug carriers, CMN possesses very high drug contents and exhibits a favorable GSH responsiveness for disassembly. Subsequently, the released MR can trigger paraptosis to cause extensive vacuolization of ER and mitochondria, contributing to activating ICD for immunotherapy. Moreover, NLG919 would inhibit IDO to remodel the tumor microenvironment and promote the activation of cytotoxic T cells, leading to an intensive antitumor immunity. Abundant in vivo studies indicate that CMN is superior in suppressing the proliferations of not only primary tumor but also metastatic and rechallenged tumors. Such a GSH-responsive paraptosis inducer might provide a promising strategy to trigger ICD and enhance tumor immunotherapy.

更新日期：2023-05-18

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