Phenolic immunogenic cell death nanoinducer for sensitizing tumor to PD-1 checkpoint blockade immunotherapy

Abstract

A critical challenge remains in PD-1 checkpoint blockade immunotherapy is few tumor specific T cells infiltration in hypoxic tumor microenvironment (TME). Improving immunogenic cell death (ICD) associated immunogenicity can make tumor sensitive to PD-1 checkpoint blockade immunotherapy. Herein, a phenolic ICD inducer was engineered by self-assembly of the superior ICD inducer (doxorubicin, DOX), phenolic manganese dioxide nanoreactor, ferric iron and PEG-polyphenols (MDP NPs) via metal phenolic coordination. These oxygen self-supporting MDP NPs strengthen DOX based ROS-dependent cell death and their metal mediated chemodynamic effect accelerate ICD induction. Together with concomitant ICD triggered by DOX, MDP NPs successively lead to tumor-associated antigen boosting, DCs maturation and ultimately enhance tumor-specific T cells infiltration. Furthermore, MDP NPs efficiently modulated hypoxic TME for effective macrophages recruitment. This promising ICD-augment strategy efficiently improve tumor response to PD-1 checkpoint blockade immunotherapy, resulting in a significant antitumor immune response in primary tumor and a strong abscopal effect to distant tumor. Our simple and versatile phenolic inducer expands the application of chemodrugs based ICD enhancing PD-1 checkpoint blockade immunotherapy.

Keywords: Immunogenic cell death; Metal phenolic coordination; PD-1 immune checkpoint blockade immunotherapy; Phenolic nanoplatform.