School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China.
School of Medicine, South China University of Technology, Guangzhou 510006, China.
J Am Chem Soc. 2024 Oct 23;146(42):29189-29198. doi: 10.1021/jacs.4c11636. Epub 2024 Oct 10.
Immunogenic cell death (ICD) has been widely employed to potentiate cancer immunotherapy due to its capability to activate the anticancer immune response. Although various ICD inducers have been described, the development of synthetic materials with intrinsic ICD-inducing competency has rarely been reported. Herein, we identify a derivative of the fourth generation polyamidoamine (PAMAM) modified with multiple seven-membered heterocyclic rings, G4P-C7A, as a robust ICD inducer. G4P-C7A evokes characteristic release of damage-associated molecular patterns in tumor cells and induces efficient dendritic cell maturation. Mechanistic studies suggest that G4P-C7A can selectively accumulate in the endoplasmic reticulum and mitochondria to generate reactive oxygen species. G4P-C7A-treated tumor cells can work as potent vaccines to protect against secondary tumor implantation. Either local or systemic injection of G4P-C7A alone can effectively inhibit tumor growth by eliciting robust antitumor immune response. The combination of G4P-C7A with immunotherapeutic antibodies such as anti-PD1 (aPD-1) and anti-CD47 (aCD47) further potentiates the antitumor effect in either CT26 or 4T1 tumor model. This study offers a simple but effective strategy to induce ICD to boost cancer immunotherapy.
免疫原性细胞死亡（ICD）因其能够激活抗肿瘤免疫反应而被广泛用于增强癌症免疫疗法。尽管已经描述了各种 ICD 诱导剂，但具有内在 ICD 诱导能力的合成材料的开发很少有报道。在此，我们确定了一种经过多次七元杂环修饰的第四代聚酰胺胺（PAMAM）衍生物 G4P-C7A，它是一种强大的 ICD 诱导剂。G4P-C7A 会引起肿瘤细胞中特征性的损伤相关分子模式的释放，并诱导有效的树突状细胞成熟。机制研究表明，G4P-C7A 可以选择性地在内质网和线粒体中积累以产生活性氧。用 G4P-C7A 处理的肿瘤细胞可以作为有效的疫苗，以防止二次肿瘤植入。单独局部或全身注射 G4P-C7A 可以通过引发强烈的抗肿瘤免疫反应有效抑制肿瘤生长。G4P-C7A 与免疫治疗抗体（如抗 PD1（aPD-1）和抗 CD47（aCD47））联合使用，在 CT26 或 4T1 肿瘤模型中进一步增强了抗肿瘤作用。这项研究提供了一种简单但有效的策略来诱导 ICD 以增强癌症免疫疗法。
