A “One Arrow Three Eagle” Strategy to Improve CM‐272 Primed Bladder Cancer Immunotherapy

Abstract

Immunotherapy using an immune‐checkpoint blockade has significantly improved the 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‐1α to form a hypoxic environment. Here, a Fe³⁺ based nMOF (MIL‐53) was 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 reduce the high level of glutathione in the tumor microenvironment (TME) for enhancing reactive oxygen species, inclucing 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 enhanced dendritic cell maturation and synergistically combined 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.

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