A "One Arrow Three Eagle" Strategy to Improve CM-272 Primed Bladder Cancer Immunotherapy

摘要

Immunotherapy using an immune-checkpoint blockade has significantly improved its therapeutic effects. CM-272, which is a novel epigenetic inhibitor of G9a, induces immunogenic cell death (ICD) for recovering the sensitivity to anti-PD-1 antibodies; however, the efficacy of CM-272 is greatly limited by promoting the transcription activity of HIF-1 alpha to form a hypoxic environment. Here, a Fe3+-based nanoscale metal-organic framework (MIL-53) is used to load CM-272 (ultra-high loading rate of 56.4%) for realizing an MIL-53@CM-272 nanoplatform. After entering bladder cancer cells, Fe3+ not only promotes the decomposition of H2O2 into O2 for O2-compensated sonodynamic therapy but reduces the high level of glutathione in the tumor microenvironment (TME) for enhancing reactive oxygen species, including ferroptosis and apoptosis. MIL-53 carriers can be degraded in response to the TME, accelerating the release of CM-272, which helps achieve the maximum effectiveness in an O2-sufficient TME by attenuating drug resistance. Furthermore, MIL-53@CM-272 enhances dendritic cell maturation and synergistically combines it with an anti-programmed cell death protein 1 antibody during the study of immune-related pathways in the transcriptomes of bladder cancer cells using RNA-seq. This study presents the first instance of amalgamating nanomedicine with CM-272, inducing apoptosis, ferroptosis, and ICD to achieve the "one arrow three eagle" effect. @@@ MIL-53@CM-272 cannot only promote the decomposition of H2O2 into O2 for O2-compensated SDT but also reduce the high level of GSH to enhance the reactive oxygen species, inducing ferroptosis and apoptosis. Significantly, MIL-53@CM-272 actives ICD to enhance T-cell receptor activation to better respond to ICI (alpha PD-1). Hence, this effective "one arrow three eagle" strategy improves CM-272 primed bladder cancer immunotherapy.image

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