Co-delivery of SN38 and MEF2D-siRNA via tLyp-1-modified liposomes reverses PD-L1 expression induced by STING activation in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) exhibits an immunosuppressive tumor microenvironment, leading to a low objective response rate when immune checkpoint inhibitors (ICIs) are utilized. The cGAS-STING pathway demonstrates a powerful immune stimulatory effect, nevertheless, activation of this pathway triggers an upregulation of PD-L1, which inhibits the anti-tumor function of immune cells. The present study discovered that knockdown of MEF2D by a siRNA in H22 cells decreases the expression of PD-L1. Subsequently, tLyp-1-modified liposomes were developed for the delivery of SN38 and MEF2D-siRNA. The outcomes indicated that the modification of tLyp-1 could enhance the uptake of liposomes by tumor cells. tLip/siMEF2D/SN38 liposomes can effectively knockdown the expression of MEF2D in HCC cells and reduce the expression of PD-L1 in vitro and in vivo, thereby enhancing proliferation inhibition and apoptosis induction, and effectively suppressing the growth of tumors. SN38 treatment elevated the expression of p-TBK1 and p-IRF3 in tumor tissue, signifying the activation of the cGAS-STING pathway and facilitating the maturation of dendritic cells in vitro and in vivo. At the same time, the co-delivery of MEF2D-siRNA reduced the expression of PD-L1, thereby decreasing the quantity of M2 macrophages and myeloid-derived suppressor cells (MDSCs) in tumors, increasing the number of CD4+ T cells within the tumor, and strengthening the anti-tumor immune efficacy. In conclusion, our results suggest that tLyP-1 modified, SN38- and MEF2D siRNA-loaded liposomes have the potential for the treatment of HCC and optimize the immunotherapy of HCC via STING activation.