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

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 immuno-therapy. Doxorubicin (DOX), ATP and ferrous ions (Fe2+) were co-assembled into nanosized amplifier (ADO-Fe) through p-p stacking and coordination effect. Meanwhile, phenylboric acid-polyethylene gly-col-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 multifunc-tional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.

Automated summary

A versatile ICD amplifier was developed to enhance tumor immunotherapy by amplifying the eat me signal during tumor immunogenic cell death cascade. The amplifier enables chemotherapy-sensitized immuno-therapy and activates immune response against tumors.