Bimodal accurate H2O2 regulation to equalize tumor-associated macrophage repolarization and immunogenic tumor cell death elicitation

Abstract

Simultaneous implementation of tumor-associated macrophage (TAM) repolarization and immunogenic tumor cell death (ICD) elicitation enables tumor immunotherapy with high efficacy. However, the inconsistency of stimulation tolerance restricts simultaneous implementation. To address this obstacle, we validate that an H₂O₂-mediated regulatory strategy could achieve coordinated occurrences. To accomplish this, a bimodal responsive modulator is constructed, namely ZnO₂-ATM (ATM: 3-amino-1,2,4-triazole), as an immune adjuvant to coordinate the occurrence of TAM repolarization and ICD elicitation through the endo/exogenous synergistic responsive production of H₂O₂. H₂O₂ produced by ZnO₂-ATM reverses the immune-suppressive TAM from an M2 to an M1 phenotype, but induces tumor cell necrosis and promotes damage-related molecular pattern release, thereby evoking ICD. This H₂O₂-mediation bimodal responsive therapeutic strategy to induce the synergistic occurrence of TAM repolarization and ICD elicitation promotes effective immune effects against tumors, demonstrating that the ZnO₂-ATM nanoadjuvant could be expected to provide new tools and paradigms for antitumor immunotherapy.