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

Abstract

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.

Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy

“…However, clinically approved epigenetic drugs (such as azacitidine and decitabine) often exhibit limited efficacy as monotherapy for solid tumors, leading to their incorporation into combination therapies. − Unfortunately, the inclusion of epigenetic agents in these combinations frequently leads to increased toxicity, necessitating dose reduction or interruption and compromising the clinical response. − These clinical findings reiterate the emerging characteristics of epigenetic intervention in solid tumors and highlight the prudence for epigenetic drug selection. As a result, despite preliminary promising efficacy, the combinational epigenetic immunotherapy calls for more exploration to enhance the synergistic effect while minimizing the adverse effect, including broadening the selection window of epigenetic drugs and completing the role of epigenetic regulation in tumor and immune cell populations. ,, In addition, synergistic drug delivery platforms for epigenetic immunotherapy are likely to provide exciting opportunities for the development of innovative and improved cancer interventions. − …”

Hyaluronic Acid-Modified Spherical MgO2/Pd Nanocomposites Exhibit Superior Antitumor Effect through Tumor Microenvironment-Responsive Ferroptosis Induction and Photothermal Therapy

“…MgO 2 /Pd@HA NCs could be effectively accumulated in tumor sites with CD44 expression and endocytosed by tumor cells due to the specific recognition between HA and CD44. Subsequently, MgO 2 will be rapidly decomposed and plenty of H 2 O 2 will be released in mild acid and hyaluronidase overexpressed TME. , Simultaneously, Pd NPs could catalyze self-supply H 2 O 2 to generate abundant • OH and catalyze GSH into GSSG, while • OH could also consume GSH in tumor cells and disturb the defense pathways of ferroptosis resulting in accumulation of LPO and occurrence of ferroptosis. , Furthermore, the high photothermal conversion performance of Pd NPs under NIR II light can synergistically cooperate with MgO 2 /Pd@HA NCs-triggered ferroptosis for tumor inhibition, indicating that the prepared MgO 2 /Pd@HA NCs responsive to TME provide a novel and promising alternative for antitumor therapy.…”

Multifaceted Carbonized Metal–Organic Frameworks Synergize with Immune Checkpoint Inhibitors for Precision and Augmented Cuproptosis Cancer Therapy

“…Metal–organic frameworks (MOFs) have garnered significant attention in recent years owing to their structural versatility, tunable properties, and diverse range of applications. − In particular, MOF derivatives (modified versions of MOFs) have shown potential in drug delivery, diagnostic imaging, and photodynamic therapy for cancer, among other modalities. − These derivatives can be customized via surface modification, functionalization with different ligands, or the encapsulation of guest molecules. , Interestingly, carbonized MOFs (cMOFs) usually exhibit higher stability than their parent MOFs and can also maintain structural integrity within the tumor microenvironment, thus showing potential for cancer therapy. Furthermore, these MOFs also exhibit superior biocompatibility, which makes them more suitable for biomedical applications such as drug delivery and imaging. , The multifunctionality and customizability of localized carbonized MOFs make them ideal candidate platforms for targeted cancer therapy, potentially leading to advanced treatment modalities. − …”