ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. We herein report an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase (SOD)- and catalase (CAT)-like activities for renal tumor growth inhibition. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuated MDSC immunosuppression via dampening the unfolded protein response, hindered M2-TAM polarization through the ERK and STAT3 pathways, but barely affected neoplastic cells and cancer-associated fibroblasts (CAFs). Furthermore, Zr-CeO enhanced the anti-tumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, we identified reversed immunosuppressive phenotypes of MDSCs and TAMs. In addition, Zr-CeO alone or combination therapy enhanced T lymphocyte infiltration and IFN-γ production within the TME. Collectively, we provided a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers. This article is protected by copyright. All rights reserved.