Combining immune checkpoint blockade with ATP-based immunogenic cell death amplifier for cancer chemo-immunotherapy

• Published in: Acta pharmaceutica Sinica. B 2022-09, Vol.12 (9), p.3694-3709
• Main Authors: Zhang, Jiulong, Sun, Xiaoyan, Zhao, Xiufeng, Yang, Chunrong, Shi, Menghao, Zhang, Benzhuo, Hu, Haiyang, Qiao, Mingxi, Chen, Dawei, Zhao, Xiuli
• Format: Article
• Language: English
• Subjects: ATP; Coordination polymer nanoparticles; Fenton reaction; Immune checkpoint blockade; Immunogenic cell death amplifier; Original; pH/ROS sensitive; Phenylboric acid
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2022.05.008

Amplifying “eat me signal” during tumor immunogenic cell death (ICD) cascade is crucial for tumor immunotherapy. Inspired by the indispensable role of adenosine triphosphate (ATP, a necessary “eat me signal” for ICD), a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy. Doxorubicin (DOX), ATP and ferrous ions (Fe2+) were co-assembled into nanosized amplifier (ADO-Fe) through π‒π stacking and coordination effect. Meanwhile, phenylboric acid-polyethylene glycol-phenylboric acid (PBA-PEG-PBA) was modified on the surface of ADO-Fe (denoted as PADO-Fe) by the virtue of d-ribose unit of ATP. PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction. In acidic microenvironment, PBA-PEG-PBA would dissociate from amplifier. Moreover, high H2O2 concentration would induce hydroxyl radical (·OH) and oxygen (O2) generation through Fenton reaction by Fe2+. DOX and ATP would be released from the amplifier, which could induce ICD effect and “ICD adjuvant” to amplify this process. Together with programmed death ligands 1 (PD-L1) checkpoint blockade immunotherapy, PADO-Fe could not only activate immune response against primary tumor, but also strong abscopal effect against distant tumor. Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy. Inspired by the indispensable role of adenosine triphosphate (ATP) in immunogenic cell death (ICD) cascade, a novel ICD amplifier (PADO-Fe) was developed for chemotherapy-sensitized immunotherapy. [Display omitted]