Circumventing Myeloid-Derived Suppressor Cell-Mediated Immunosuppression Using an Oxygen-Generated and -Economized Nanoplatform.

The myeloid-derived suppressor cell (MDSC)-mediated immunosuppressive tumor microenvironment (TME), where tumor hypoxia counts for much, has greatly compromised the outcome of cancer immunotherapy. Here, we demonstrated a strategy for selectively clearing intratumoral MDSCs. Specifically, 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR-780) and metformin (Met) were coloaded into mesoporous silica nanoparticles (MSNs) with CeO as the gatekeepers. Controlled release of cargos was achieved upon etching CeO with endogenous HO. Apart from the drug release, oxygen (O) was also generated in this process. Importantly, the engagement of Met significantly inhibited mitochondrial respiration, thus working like an O economizer. Consequently, the populations and functions of tumor-infiltrated MDSCs were both dramatically reduced through selective alleviation of hypoxia at tumor sites, thus contributing to boosted immune responses. Additionally, the accumulated O enhanced IR780-mediated photodynamic therapy, which synergistically strengthened the antitumor efficacy of the platform. To the best of our knowledge, this is the first time to employ an O-generated and -economized nanoplatform for selectively anergizing MDSC-mediated immunosuppression. We expect that this strategy will shed new light on the clinical cancer immunotherapy treatment.