Copper homeostasis and cuproptosis in cancer immunity and therapy

Abstract

SummaryCopper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.

Ferredoxin 1: a gatekeeper in halting lung adenocarcinoma progression through activation of the GPRIN2 signaling pathway

“…Cuproptosis has been implicated in various pathological conditions, including neurodegenerative diseases, liver diseases, and cancer [ 19 ]. Dysregulated copper metabolism and cuproptosis are evident in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, where the accumulation of copper in specific brain regions contributes to neuronal cell death [ 20 , 21 ]. In the context of cancer, dysregulated copper transporters and copper chelation have shown promise in inducing cuproptosis as a potential therapeutic strategy [ 22 – 25 ].…”

Cuproptosis in stroke: focusing on pathogenesis and treatment

“…When comparing ferroptosis and cuproptosis, it is clear that mitochondria play a critical role in both types of cell death. Dihydrolipamide S-acetyltransferase (DLAT) ( Liu et al, 2024 ) is central to this process. Copper directly binds to DLAT, promoting the formation of disulfide bonds in fatty acylated DLAT, which triggers cell death.…”

Research progress on cuproptosis in cancer

“…Several copper chelators have been used to reduce copper bioavailability, including D-penicillamine, tetrathiomolybdate (TM), and tetraethylenepentamine (TEPA) ( Liu et al, 2023 ). Inhibitors of oxidative phosphorylation suppress cuproptosis by inhibiting protein stress response.…”