ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy

Abstract

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. Herein, an ROS scavenging nanozyme, Zr‐CeO, with enhanced superoxide dismutase‐ and catalase‐like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr‐CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2‐TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer‐associated fibroblasts. Furthermore, Zr‐CeO enhances the antitumor 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, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr‐CeO alone or combination therapy enhances T lymphocyte infiltration and IFN‐γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.

Role played by MDSC in colitis-associated colorectal cancer and potential therapeutic strategies

“…Against hypoxia, a phase 1/2 clinical study (NCT01522872) involving TH-302 (efaproxiral), a hypoxia-activated prodrug, demonstrated extended survival in patients with myeloma, combating the effects of hypoxia (Laubach et al 2019 ). In mouse kidney and mammary tumor models, researchers found that a nano-enzyme called Zr-CeO exhibited promising results in diminishing the recruitment of MDSCs, thereby enhancing the efficacy of PD-1 inhibitors in combating tumors (Mo et al 2023 ).…”

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“…With the development of nanotechnology, numerous studies have shown that nanozymes have the function of regulating reactive oxygen species (ROS). Based on this, nanozymes are widely used in the regulation and improvement of a variety of ROS-related diseases [ 6 – 8 ].…”

Multifunctional Cerium Oxide Nanozyme for Synergistic Dry Eye Disease Therapy

“…33 Recently, a Zr-CeO nanozyme with an enhanced ratio of Ce 3+ /Ce 4+ was successfully prepared to improve the tumor microenvironment by scavenging intracellular ROS. 34 In our previous studies, a cerium oxide nanozyme with good water solubility, stability, and antioxidant properties was successfully constructed via taking branched polyethylenimine-graft-poly(ethylene glycol) (bPEI-g-PEG) as nucleating and dispersing agents. 35 In this study, the bPEI-g-PEG based cerium oxide nanoparticles (Ce@P) were first phenylboronated by chemical grafting of 3-carboxyphenylboronic acid (PBA) via carbodiimide chemistry, and the DQS was then conjugated onto the PBA functionalized Ce@P (Ce@PB) surface via dynamic phenylborate ester bond due to its cis-diol structure, obtaining the DQS-loaded cerium oxide nanozyme (defined as Ce@PBD) (Figure 1).…”