Enhanced chemodynamic therapy and immunotherapy by hypoxia augmentation for tumor ablation

Chemodynamic therapy (CDT) produces highly toxic hydroxyl free radicals (•OH) to achieve selective tumor treatment based on Fenton reaction. However, the insufficient intracellular H2O2 level in tumor cells severely limits the therapeutic efficacy of Fenton reaction. Here, we report a synergistic enhancement strategy for amplifying Fenton reaction and relieving the tumor immunosuppressive microenvironment. In this work, a targeted PCL-PEG-cRGD (PCE-cRGD) micelle was developed for delivering apatinib (APA) to tumor vessels, promoting vascular normalization and relieving tumor hypoxia. On one hand, the hypoxia relief promoted the chemodynamic therapy of ascorbyl palmitate-loaded FePOs, where ascorbyl palmitate generates endogenous H2O2 in the presence of oxygen, and FePOs catalyze Fenton reaction to produce more potent •OH, which can be reduced to Fe2+ by ascorbyl palmitate. The continued involvement of Fe2+ in the Fenton reaction enhances tumor therapy efficiency through cyclic catalysis and self-enhanced catalysis. On the other hand, the increased oxygen content induced the polarization of M2 macrophage to antitumor M1 phenotype, which secreted TNF-α and IL-6 to activate CD4+ and CD8+ T cells, enhancing antitumor immune response. Combining enhanced chemodynamic therapy and immunotherapy, this strategy establishes the high feasibility of the synergistic treatment concept.