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-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.

中文翻译：

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改善 CM-272 引发的膀胱癌免疫治疗的“一箭三鹰”策略

使用免疫检查点阻断的免疫疗法显着提高了其治疗效果。CM-272是一种新型G9a表观遗传抑制剂，可诱导免疫原性细胞死亡（ICD）以恢复​​对抗PD-1抗体的敏感性；然而，CM-272通过促进HIF- 1α转录活性形成缺氧环境，其功效受到极大限制。这里，使用Fe ³⁺基纳米级金属有机框架（MIL-53）来负载CM-272（超高负载率56.4％），以实现MIL-53@CM-272纳米平台。进入膀胱癌细胞后，Fe ^{3+不仅促进 H} ₂ O ₂分解为 O ₂以进行 O ₂补偿声动力治疗，而且降低肿瘤微环境 (TME) 中的高水平谷胱甘肽以增强活性氧，包括铁死亡和细胞凋亡。MIL-53载体可以响应TME而被降解，加速CM-272的释放，这有助于通过减弱耐药性在O _{2充足的TME中实现最大效力。}此外，在使用 RNA-seq 研究膀胱癌细胞转录组中的免疫相关通路时，MIL-53@CM-272 可以增强树突状细胞的成熟，并与抗程序性细胞死亡蛋白 1 抗体协同结合。该研究首次将纳米药物与CM-272结合，诱导细胞凋亡、铁死亡和ICD，以达到“一箭三鹰”的效果。