Nucleic acid/cyanine composite nanomedicine for targeted remote tumor therapy to counteract RT-induced immunosuppression

Abstract

Although radiotherapy (RT) can enhance T cell priming by inducing in-situ tumor vaccines, it is essential to acknowledge that the immunosuppression resulting from RT, characterized by the infiltration of myeloid-derived suppressor cells (MDSCs) and the upregulation of PD-L1, attenuates T cell effector function and exacerbates distant tumors and metastatic lesions. In this study, we synthesized a novel iodine-incorporated cyanine dye, designated Cy-I, and co-encapsulated CpG with Cy-I within T cell membrane fusion liposomes to create an innovative composite nanomedicine referred to as CIFL. We established bilateral tumor and lung metastasis models, followed by intravenous administration of CIFL. Our results indicate that CIFL enhances the efficacy of RT while promoting the generation of tumor vaccines and activating T cells. Notably, RT-induced upregulation of PD-L1 in distal tumors enhances the distal tumor targeting of CIFL, enabling it to effectively inhibit the expression of PD-L1 in distal tumors and block the function of MDSCs. The combinatorial treatment of CIFL and RT not only enhances primary tumor treatment but also suppresses distal tumor metastatic growth, and reverses immunosuppression in distal tumors post-RT. This therapeutic strategy demonstrates significant promise for clinical translation.