A STING pathway-activatable contrast agent for MRI-guided tumor immunoferroptosis synergistic therapy

Abstract

The immunotherapy efficiency of stimulator of interferon genes (STING)-activatable drugs (e.g., 7-ethyl-10-hydroxycamptothecin, SN38) is limited by their non-specificity to tumor cells and the slow excretion of the DNA-containing exosomes from the treated cancer cells. The efficacy of tumor ferroptosis therapy is always limited by the elimination of lipid peroxides (LPO) by the pathways of glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH) and ferroptosis suppressor protein 1(FSP1). To solve these problems, in this study, we developed a STING pathway-activatable contrast agent (i.e., FeGd-HN@TA-Fe²⁺-SN38 nanoparticles) for magnetic resonance imaging (MRI)-guided tumor immunoferroptosis synergistic therapy. The remarkable in vivo MRI performance of FeGd-HN@TA-Fe²⁺-SN38 is attributed to its high accumulation at tumor location, the high relaxivities of FeGd-HN core, and the pH-sensitive TA-Fe²⁺-SN38 layer. The effectiveness and biosafety of the immunoferroptosis synergistic therapy induced by FeGd-HN@TA-Fe²⁺-SN38 are demonstrated by the in vivo investigations on the 4T1 tumor-bearing mice. The mechanisms of in vivo immunoferroptosis synergistic therapy by FeGd-HN@TA-Fe²⁺-SN38 are demonstrated by measurements of in vivo ROS, LPO, GPX4 and SLC7A11 levels, the intratumor matured DCs and CD8⁺ T cells, the protein expresion of STING and IRF-3, and the secretion of IFN-β and IFN-γ.

Keywords: Contrast agents (CAs); Enhanced ferroptosis therapy; Immunoferroptosis synergistic therapy; Magnetic resonance imaging (MRI); Stimulator of interferon genes (STING).