AbstractImmunotherapy 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‐1α 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.
