Near-infrared Activatable Copper Nanoplatforms Synergize with the 5-Azacytidine Prodrug to Potentiate Cuproptosis.

Cuproptosis, a newly discovered cell death modality, is gaining recognition for its crucial role in antitumor therapy. Here, we demonstrated that Ferredoxin 1 (FDX1), a key gene involved in cuproptosis, is negatively correlated with malignancy and T-cell exhaustion in head and neck squamous cell carcinoma (HNSCC). Based on these findings, we developed near-infrared (NIR) light-controlled nanoparticles (NPs), CuD@PM, which can selectively deliver copper to HNSCC cells and induce cuproptosis in the presence of microneedles loaded with triacetylated azacitidine (TAc-AzaC) and 808 nm laser irradiation. Intravenous administration of these NPs significantly suppressed tumor growth in HNSCC animal models and enhanced the antitumor immune response. The NIR-controlled activation of cuproptosis offers great potential as a safe, targeted, and image-guided antitumor therapy for HNSCC.

Dysregulated Wnt/ß-catenin signaling confers resistance to cuproptosis in cancer cells.

Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/ß-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/ß-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/ß-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the ß-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/ß-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/ß-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

Cuproptosis: Harnessing Transition Metal for Cancer Therapy.

Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to regulate the proliferation and metastasis of tumors, and are integral components of metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate the occurrence of programmed cell death (PCD), known as cuprotosis, in cancer cells. This modulation occurs through the disruption of tumor cell metabolism and the induction of proteotoxic stress. This discovery uncovers a mode of interaction between transition metals and proteins, emphasizing the intricate link between copper homeostasis and tumor metabolism. Moreover, they provide innovative therapeutic strategies for the precise diagnosis and treatment of malignant tumors. At the crossroads of chemistry and oncology, we undertake a comprehensive review of copper homeostasis in tumors, elucidating the molecular mechanisms underpinning cuproptosis. Additionally, we summarize current nanotherapeutic approaches that target cuproptosis and provide an overview of the available laboratory and clinical methods for monitoring this process. In the context of emerging concepts, challenges, and opportunities, we emphasize the significant potential of nanotechnology in the advancement of this field.

Activation of Pyroptosis Using AIEgen-Based sp2 Carbon-Linked Covalent Organic Frameworks.

Covalent organic frameworks (COFs) have emerged as a promising class of crystalline porous materials for cancer phototherapy, due to their exceptional characteristics, including light absorption, biocompatibility, and photostability. However, the aggregation-caused quenching effect and apoptosis resistance often limit their therapeutic efficacy. Herein, we demonstrated for the first time that linking luminogens with aggregation-induced emission effect (AIEgens) into COF networks via vinyl linkages was an effective strategy to construct nonmetallic pyroptosis inducers for boosting antitumor immunity. Mechanistic investigations revealed that the formation of the vinyl linkage in the AIE COF endowed it with not only high brightness but also strong light absorption ability, long lifetime, and high quantum yield to favor the generation of reactive oxygen species for eliciting pyroptosis. In addition, the synergized system of the AIE COF and αPD-1 not only effectively eradicated primary and distant tumors but also inhibited tumor recurrence and metastasis in a bilateral 4T1 tumor model.

Inhibition of DNMT1 potentiates antitumor immunity in oral squamous cell carcinoma.

Epigenetic alterations, including DNA methylation, play crucial roles in the tumor. Epigenetic drugs like DNA methyltransferase-1 (DNMT1) inhibitors have been exhibited positive effects in cancer treatment. However, the role of DNMT1 in oral squamous cell carcinoma (OSCC) is less clearly described. What is more, the effects on the immune microenvironment of DNMT1 have not become appreciated. In this research, we determine the expression levels of DNMT1 and the association of prognosis by analyzing human OSCC tissue microarrays. Two different types of immunocompetent mouse OSCC models were established to explore the effects of DNMT1 inhibitor on the tumor microenvironment(TME). We identified DNMT1 was highly expressed both in human and mouse OSCC tissues. The expression levels of DNMT1 was also correlated with the immunosuppressive molecules and tumor-promoter such as VISTA, PD-L1, B7-H4, and PAK2, indicating a worse prognosis. Of particular concern is that DNMT1 inhibition improved TME and delayed tumor growth by decreasing myeloid-derived suppressor cells (MDSCs) and increasing tumor-infiltrating T cells. Our data suggests that DNMT1 play a key role in OSCC and has a possible immunotherapeutic marker treatment.

Eliciting pyroptosis to fuel cancer immunotherapy: mechanisms and strategies.

Immune checkpoint blockade (ICB) therapy has recently shown promise in treating several malignancies. However, only a limited number of patients respond to this treatment, partially because of the "immune cold" condition of the tumor immune microenvironment. Pyroptosis is a type of gasdermin-mediated programmed cell death that often leads to inflammation and immune responses. Many studies on the mechanism and function of pyroptosis have led to increasing recognition of the role of pyroptosis in malignant progression and immune therapy. Pyroptosis has the potential to alter the tumor immune microenvironment by releasing tumor-associated antigens, damage-associated molecular patterns, and proinflammatory cytokines, thus leading to intratumoral inflammatory responses, stimulation of tumor-specific cytotoxic T cell infiltration, conversion of "cold" to "hot" tumors, and ultimately improving the efficacy of ICB therapy. Some cancer treatments have been shown to restore anticancer immunosurveillance through the induction of pyroptosis. Therapy promoting pyroptosis and ICB therapy may have synergistic effects in cancer treatment. This review summarizes the mechanisms and roles of pyroptosis in the tumor microenvironment and combination treatment strategies. An improved understanding of the roles of pyroptosis in tumorigenesis, immune evasion, and treatment would aid in the development of therapeutic strategies for malignancies.

Down-regulation of Spinal 5-HT2A and 5-HT2C Receptors Contributes to Somatic Hyperalgesia induced by Orofacial Inflammation Combined with Stress.

Patients suffering with functional somatic pain syndromes such as temporomandibular disorders (TMD) and fibromyalgia syndrome (FMS) have some similar symptoms, but the underlying cause is still unclear. The purpose of this study was to investigate whether 5-HT2A and 5-HT2C receptors in the spinal cord contribute to somatic hyperalgesia induced by orofacial inflammation combined with different modes of stress. Ovariectomized rats were injected subcutaneously with estradiol and bilateral masseter muscles were injected with complete Freund's adjuvant followed by stress. Somatic sensitivity was assessed with thermal and mechanical stimulation. The anxiety- and depression-like behaviors were measured by immobility time, sucrose preference, elevated plus maze and open field tests. The expression of 5-HT2A and 5-HT2C receptors in the spinal cord was examined by Western blot. Orofacial inflammation combined with 11 day forced swim stress (FSS) induced persistent mechanical allodynia for 15 days and thermal hyperalgesia for 2 days. The mechanical and thermal hyperalgesia lasted for 43 days and 30 days respectively following orofacial inflammation combined with 11 day heterotypic stress. Orofacial inflammation combined with stress induced anxiety- and depression-like behaviors. The expression of 5-HT2A and 5-HT2C receptors significantly decreased in the orofacial inflammation combined with stress groups. Intrathecal injection of 5-HT2A or 5-HT2C receptor agonist reversed somatic hyperalgesia. The results suggest that down-regulation of 5-HT2A and 5-HT2C receptors in the spinal cord contributes to somatic hyperalgesia induced by orofacial inflammation combined with stress, indicating that 5-HT2A and 5-HT2C receptors may be potential targets in the treatment of TMD comorbid with FMS.