Cuproptosis: Harnessing Transition Metal for Cancer Therapy

Abstract

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.

Design of Near Infrared Light‐Powered Copper Phyllosilicate Nanomotors for Cuproptosis‐Based Synergistic Cancer Therapy

“…[37] In addition, the discovery of cuproptosis provides a new insight for the design of copper phyllosilicate nanomedicines. [38,39] Cuproptosis is a newly discovered cell death pathway, which was first proposed by Tsvetkov et al in 2022. [40] Specifically, the accumulated copper ions within cells directly bind to lipoylated components of the tricarboxylic acid (TCA) cycle, [41] leading to the aggregation of lipoylated proteins (especially dihydrolipoamide S-acetyltransferase, DLAT) and the downregulation of iron-sulfur cluster protein expression, which induce protein toxicity stress and ultimately cause cell death.…”

Coordination Self-Assembled AuTPyP-Cu Metal–Organic Framework Nanosheets with pH/Ultrasound Dual-Responsiveness for Synergistically Triggering Cuproptosis-Augmented Chemotherapy

“…Compared to the most studied Fe-based type CDT, a Cu + -catalyzed Fenton-like reaction has higher catalytic efficiency (160-fold) in both acidic and neutral conditions. , As a recently discovered copper-dependent cell death paradigm, cuproptosis is characterized by Ferredoxin 1 (FDX1) and is different from the common cell death modes, e.g., apoptosis, necroptosis, and autophagy. − As documented, FDX1 reduces Cu 2+ to more toxic Cu + and inhibits the biosynthesis of the Fe–S cluster protein. Cu 2+ also promotes the aberrant aggregation of dihydrolipoamide acetyltransferase (DLAT), , leading to proteotoxic stress (the upregulation of stress-induced heat shock proteins such as HSP70). This cascade of events results in cell membrane ruptures, endoplasmic reticulum damage, impaired mitochondrial function, and ultimately cell death.…”

“…10−12 As documented, FDX1 reduces Cu 2+ to more toxic Cu + and inhibits the biosynthesis of the Fe−S cluster protein. Cu 2+ also promotes the aberrant aggregation of dihydrolipoamide acetyltransferase (DLAT), 13,14 leading to proteotoxic stress (the upregulation of stress-induced heat shock proteins such as HSP70). This cascade of events results in cell membrane ruptures, endoplasmic reticulum damage, impaired mitochondrial function, and ultimately cell death.…”

Monitoring the Mitochondrial Viscosity Changes During Cuproptosis with Iridium(III) Complex Probe via In Situ Phosphorescence Lifetime Imaging

“…Cuproptosis is a novel copper-dependent form of programmed cell death (PCD) closely related to mitochondrial respiration, which is different from other known PCD pathways such as apoptosis, autophagy, necroptosis, pytoptosis, and ferroptosis . Cuproptosis occurs by the direct binding of copper ions with lipoylated components in the tricarboxylic acid (TCA) cycle, which induces the aggregation of lipoylated proteins and the loss of iron–sulfur cluster proteins, thus resulting in subsequent proteotoxic stress and eventually cell death. , Currently, increasing evidence demonstrates that cuproptosis is associated with a host of diseases such as Wilson’s disease, neurodegenerative disease, and cancer . In-depth investigation on cuproptosis contributes to the development of effective disease treatment technologies and is of great significance for basic biological research as well as pharmaceutical development and medical diagnosis.…”