Tumor Microenvironment-Activable Manganese-Boosted Catalytic Immunotherapy Combined with PD-1 Checkpoint Blockade

Abstract

Immune checkpoint blockade (ICB) therapy has attracted widespread attention in cancer treatment. Due to the low immunogenicity and immune suppression state in the tumor microenvironment (TME), the therapeutic effects are only moderate. Herein, a TME-activable manganese-boosted catalytic immunotherapy is designed for synergism with ICB therapy to kill tumors efficiently. The tumor cell membrane (CM)-wrapping multienzyme-mimic manganese oxide (MnO_x) nanozyme termed CM@Mn showed intrinsic peroxidase and oxidase-like activities in an acidic TME. These activities can generate toxic hydroxyl (^•OH) and superoxide radicals (^•O₂^-) for tumor cell killing and evoking immunogenic cell death (ICD). Furthermore, the TME-responsive release of Mn²⁺ directly promotes dendritic cell maturation and macrophage M1 repolarization, resulting in the reversal of an immunosuppressive TME into an immune-activating environment. Additionally, tumor hypoxia relief caused by catalase-like activity also contributes to the process of TME reversal. Finally, a robust tumor-specific T cell-mediated antitumor response occurs with the support of the PD-1 checkpoint blockade. The proliferation of primary and metastatic tumors was inhibited, and a long-term immune memory effect was induced. The therapeutic strategy outlined here may serve as a promising candidate for tumor-integrated treatment.

Keywords: catalytic immunotherapy; immune activation; immune checkpoint blockade; immunogenic cell death; manganese.