Interfering tumor metabolism by bimetallic nanoagent for amplifying nanocatalytic-mediated glioblastoma immunotherapy

Abstract

Glioblastoma is a malignant tumor with a high recurrence rate and a profound immunosuppressive microenvironment that makes immunotherapy ineffective. Herein, an iron-copper bimetallic nanoagent (NMCuA) grafted with blood–brain barrier (BBB) cells targeting peptide angiopep-2 and loaded indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor (NLG919) for remodulating the immunosuppressive microenvironment to enhance the therapeutic efficiency of glioblastoma immunotherapy is demonstrated. Such NMCuA can synergistically amplify nanocatalytic-mediated glioblastoma immunotherapy by interfering with amino acid metabolism. Briefly, Cu/Fe released from the nanoagent undergoes a catalytic reaction to generate cytotoxic hydroxyl radicals (•OH) in the acidic tumor microenvironment (TME), leading to intracellular lipid peroxidation (LPO). Meanwhile, Cu2+ also chelates with excess cysteine (Cys), resulting in glutathione (GSH) depletion and glutathione peroxidase 4 (GPX4) inactivation, further promoting LPO accumulation. In addition, IDO1-mediated tryptophan metabolic pathway is inhibited by NLG919, thus contributing to the reduction of Treg cells (Tregs) accumulation and •OH clearance. Therefore, interfering tumor metabolism enhances metal-based catalytic therapy, which further strengthens •OH burst and intracellular LPO accumulation, thereby triggering an effective immunogenic cell death (ICD) process. This bimetallic nanoagent activates the body to generate a powerful immune response that can significantly inhibit in situ tumor growth and reversing the immunosuppressive TME. Furthermore, the nanoagent can generate effective immune memory effects by combining immune checkpoint inhibitor, thereby suppressing glioblastoma recurrence.