Application Of Iron Metal Oxygen Clusters In Radiokinetics/immunotherapy

Radiation therapy(RT),as one of the most effective local tumor treatment methods,has been widely used in the clinical treatment of tumor patients.RT can directly cause DNA damage in tumor cells through high-energy ionizing radiation,or indirectly interact with water molecules to generate hydroxyl radicals(·OH),thereby causing tumor cell death.However,substantial clinical and preclinical evidence suggests that tumor cells have low immunogenicity and only a few T cells in the body can recognize tumor cells.Due to the low absorption of ionizing radiation by hypoxic tumors,radiotherapy alone generates less reactive oxygen species(ROS)and can only induce low levels of immunogenic cell death(ICD),failing to achieve antigen presentation and antitumor immune activation.Therefore,amplifying oxidative stress-induced ICD to initiate an immune response is a good strategy to improve the effect of RT.At the same time,combined with checkpoint blockade immunotherapy(CBI),T cell viability is restored by targeting immune checkpoints with immune checkpoint inhibitors,thereby enhancing the systemic antitumor immune response.This strategy to improve the effect of radioimmunotherapy can induce distal effects and inhibit the growth of both primary and distant tumors to a certain extent.In this paper,we synthesized an iron metal-oxygen cluster compound K₂₁Na₈[KFe₁₂(OH)₁₈(?-1,2,3-P₂W₁₅O₅₆)₄]·70H₂O(Fe₁₂-POM)with ultra-small molecular size(3 nm)and good water solubility.Solution experiments show that in the presence of hydrogen peroxide(H₂O₂),the compound can undergo a Fenton reaction to produce·OH.At the same time,the Fe₁₂-POM structure contains tungsten atoms with high atomic number,which act as radiosensitizer to increase the X-ray energy deposition and promote RT to generate more·OH.More importantly,we demonstrated that under X-ray irradiation,intramolecular electron transfer occurred in the Fe₁₂-POM structure,resulting in the partial conversion of Fe³⁺to Fe²⁺,which promoted the chemodynamic therapy effect and realized radiodynamic therapy(RDT).Cellular experiments further demonstrated that the combined action of Fe₁₂-POM and X-ray amplified oxidative stress,effectively induced ICD,and promoted the maturation of dendritic cells and the infiltration of T cells.Finally,in vivo experiments combined with immune checkpoint inhibitor?-PD-1 synergistic therapy triggered systemic antitumor immunity and inhibited the growth of both in situ and distant tumors.