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

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-2H-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 CeO₂ as the gatekeepers. Controlled release of cargos was achieved upon etching CeO₂ with endogenous H₂O₂. Apart from the drug release, oxygen (O₂) was also generated in this process. Importantly, the engagement of Met significantly inhibited mitochondrial respiration, thus working like an O₂ 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 O₂ 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 O₂-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.