CXCR4-targeted nanoparticles co-delivering sorafenib and MEK-inhibitors modulate the immunosuppressive tumor microenvironment in hepatocellular carcinoma Yunching Chen1,*, Ya-Chi Liu1,† and Dan G. Duda2,* 1Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan; 2Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Inhibition of RAF with anti-cancer drugs may induce a paradoxical upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway, i.e., the RAF/MEK/ERK signal transduction cascade in cancer cells. Sorafenib is a RAF inhibitor approved for advanced hepatocellular carcinoma (HCC). Here, we demonstrate that RAF sorafenib rapidly induces RAF dimerization and ERK activation in HCCs, which promotes treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and modulate the immunosuppressive tumor microenvironment, we develop CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Sorafenib and MEK inhibitor loaded in CXCR4-targeted NPs efficiently down-regulate RAF/ERK and PD-L1 expression, facilitate intra-tumoral infiltration of cytotoxic CD8+ T cells, and trigger T cell activation in HCC, leading to a profound delay in tumor growth.
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