Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Abstract

their quality of life. [1] Despite local therapy, approximately one-third of patients will relapse and develop metastatic diseases. [2] In recent years, immunotherapy has made great progress. Anti-programmed cell death protein ligand-1 antibody (αPD-L1) has been approved by the US Food and Drug Administration for bladder cancer treatment since 2016, the usage of which spanning from non-muscle-invasive to metastatic disease. [3] However, many bladder cancer patients fail to respond to these treatments. [4] On the one hand, many tumors are immune "cold tumors" with an immunosuppressive tumor microenvironment (TME) that do not respond to existing immunotherapeutic agents. [5] On the other hand, αPD-L1 is a viable choice only for programmed cell death proteinligand 1 (PD-L1) positive bladder cancer patients, while PD-L1 expression varies between individuals. [6] Recent studies indicated that intra-tumoral copper (Cu) levels in tumors could affect PD-L1 expression, but enhancing the effect of αPD-L1 by regulating Cu levels has not been reported in vivo studies so far. [7] Cu is an extremely important intracellular trace element that plays a key role in maintaining redox Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces cell death. However, existingCu ionophores are small molecules with a short blood half-life making it hard to transport enough Cu into cancer cells. Herein, a reactive oxygen species (ROS)-sensitive polymer (PHPM) is designed, which is used to co-encapsulate elesclomol (ES) and Cu to form nanoparticles (NP@ESCu). After entering cancer cells, ES and Cu, triggered by excessive intracellular ROS, are readily released. ES and Cu work in a concerted way to not only kill cancer cells by cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu to efficiently transport Cu and induce cuproptosis is investigated. In addition, the change in the transcriptomes of cancer cells treated with NP@ESCu is explored by RNA-Seq. In vivo, NP@ESCu is found to induce cuproptosis in the mice model with subcutaneous bladder cancer, reprograming the tumor microenvironment. Additionally, NP@ESCu is further combined with anti-programmed cell death protein ligand-1 antibody (αPD-L1). This study provides the first report of combining nanomedicine that can induce cuproptosis with αPD-L1 for enhanced cancer therapy, thereby providing a novel strategy for future cancer therapy.

Single-Site Nanozymes with a Highly Conjugated Coordination Structure for Antitumor Immunotherapy via Cuproptosis and Cascade-Enhanced T Lymphocyte Activity

“…Accumulation of large amounts of Cu + in cancer cells can disrupt specific mitochondrial metabolic enzymes, in particular DLAT, a subunit of the pyruvate dehydrogenase complex found in mitochondria, which mainly regulates the tricarboxylic acid cycle. Cu + binding to DLAT promotes DLAT oligomerization and increases insoluble DLAT accumulation, which further leads to proteotoxic stress and cell death. − Hence, DLAT oligomerization was further evaluated by immunofluorescence imaging. As shown in Figure j, compared with the control group, Cu-DBCO- or Cu-DBCO/C-treated 4T1 cells exhibited obvious DLAT aggregation, indicating that Cu-DBCO can promote the aggregation of lipidated proteins and ultimately induce cell death by cuproptosis.…”

Immunoactivity of a hybrid membrane biosurface on nanoparticles: enhancing interactions with dendritic cells to augment anti-tumor immune responses

“…94–96 In this study, an additional combination of immune checkpoint blocking (ICB) treatment, e.g. administration of PD-1 or PD-L1 antibodies, 97–99 may be able to further enhance the anti-tumor effects, which may deserve more investigations in the future. Tumors harvested from mice treated with HMPR displayed the smallest size (Fig.…”

An Intelligent Cupreous Nanoplatform with Self-Supplied H2O2 and Cu2+/Cu+ Conversion to Boost Cuproptosis and Chemodynamic Combined Therapy

“…Since first reported in 2022, this copper-dependent cuproptosis has sparked tremendous attention in cancer therapy and a few studies of cuproptosis-based cancer therapy have recently been reported. ,, However, the application of cuproptosis in tumor treatment suffers from several challenges: (a) the intracellular copper level was too low to realize therapeutic activity, (b) nonselectivity and potential systemic toxicity of copper ions resulted in off-target toxicities and unpredictable side effects, , and (c) there is difficulty in transporting free copper ions into cancer cells because excess copper ions were discharged out of the cells through copper exporters like ATP7A and ATP7B . Given the circumstances, increasing the copper level in cancer cells by selective delivery of exogenous copper ions was expected to promote cuproptosis and avoid potential toxicities to healthy tissues/organs. ,,− Additionally, in comparison to Cu 2+ , Cu + was found to be preferable for cuproptosis because Cu + could directly bind to lipoylated TCA cycle proteins . Hence, how to deliver copper ions in the form of Cu + to cancer cells is also a concern in the development of effective cuproptosis therapy.…”