Sequential depletion of myeloid-derived suppressor cells and tumor cells with a dual-pH-sensitive conjugated micelle system for cancer chemoimmunotherapy

Myeloid-derived suppressor cells(MDSCs)are one of the most important immunosuppressive cells in tumor microenvironment, which also promote the development and progression of tumor cells. Nevertheless, due to the different distribution features of MDSCs and tumor cells, selective elimination of MDSCs and tumor cells in tumor microenvironment remain a great challenge. Here we have designed a dual-pH-sensitivity conjugated micelle system (PAH/RGX-104@PDM/PTX) that could deliver liver-X nuclear receptor (LXR) agonist RGX-104 and paclitaxel (PTX) to the perivascular region and tumor cells, respectively. Upon arrival at the acidic tumor microenvironment, the PAH/RGX-104@PDM/PTX undergo structure disintegration and capacitate coinstantaneous release of RGX-104 in the perivascular regions, leaving the intact PTX containing micelles PDM/PTX for tumor deep penetration. The released RGX-104 can be preferentially taken up by leukocytes, endothelial cells and macrophages which are nicely enriched in perivascular regions to active the LXR, and further reduces immunosuppressive MDSC levels. The remained small micelles carrying PTX enable deep tumor penetration as well as rapid specific drug release in the endosomal/lysosomal to kill tumor cells. PAH/RGX-104@PDM/PTX exhibits superior tumor accumulation as well as tumor penetration, and suppresses 74.88% in vivo tumor growth. More importantly, PAH/RGX-104@PDM/PTX has significantly alleviated tumor immunosuppression by eliminating MDSCs and increasing cytotoxic T lymphocytes infiltration. Our studies suggest that the dual-pHsensitive codelivery nanocarrier not only cause apoptosis of cancer cells but also regulate the tumor immune environment to ultimately enhance the antitumor effect of CTLs through MDSCs depletion.