Cuproptosis in Cancer: Mechanisms, Microenvironment, and Therapeutic Exploitation

The field of regulated cell death has undergone a transformative shift with the discovery of novel modalities beyond apoptosis, such as ferroptosis, which have redefined our understanding of cellular fate, metabolism, and disease. Most recently, cuproptosis has emerged as a copper-dependent, mitochondria-driven cell death pathway that is biochemically and morphologically distinct from known forms of cell demise. Initial studies have shown that cuproptosis is triggered by copper’s interaction with lipoylated components of the tricarboxylic acid (TCA) cycle, leading to proteotoxic stress and cell death. While copper is vital for numerous cellular functions, its dysregulation can have cytotoxic effects—a fact increasingly appreciated in the context of cancer, where aberrant copper metabolism is frequently observed. Despite rapid progress in elucidating cuproptosis mechanisms, significant gaps remain in understanding the exact molecular machinery, the influence of the tumor microenvironment, and how cuproptosis interacts with or diverges from other cell death pathways.This Research Topic aims to comprehensively dissect the role of cuproptosis in cancer biology by defining its fundamental molecular mechanisms, exploring its relationship with cellular metabolism and the tumor microenvironment, and assessing its translational relevance for therapy. Central objectives include clarifying the biochemical cascade that underlies cuproptosis initiation and execution, characterizing how copper homeostasis and transport systems predispose cancer cells to this form of death, and investigating how the tumor milieu and inter-pathway crosstalk either facilitate or restrain cuproptosis. Additionally, by interrogating the sensitivity of various cancer subtypes and stem cell populations to cuproptosis, the goal is to pinpoint potential vulnerabilities that can be leveraged therapeutically and to identify robust biomarkers for clinical application.This Research Topic is designed to encompass mechanistic, translational, and methodological aspects of cuproptosis in cancer. Contributions are expected to stay within the intersection of copper metabolism, regulated cell death, and tumor biology, while limiting focus to studies that elucidate cellular and molecular principles or have therapeutic relevance. To gather further insights into these domains, we welcome articles addressing, but not limited to, the following themes:o Molecular determinants and regulators of cuproptosis in cancer cells.o Mechanisms and consequences of altered copper metabolism in the tumor setting.o Role of the tumor microenvironment in shaping copper availability and cuproptosis activation.o Crosstalk between cuproptosis and other regulated cell death pathways.o Baseline and induced cuproptosis sensitivity across cancer subtypes and cancer stem cell contexts.o Discovery and clinical validation of predictive biomarkers for cuproptosis.o Novel therapeutic strategies aimed at inducing or modulating cuproptosis in malignancies.o Advanced methodologies for tracking copper dynamics and modeling cuproptosis networks in vitro and in vivo.Note on Scope: Manuscripts that solely report the anti-cancer effects of copper-ionophores or chelators without novel insights into the mechanism of cuproptosis or copper biology in cancer cells fall outside the journal's scope. Purely bioinformatic analyses of public datasets must include experimental validation. Topic editors: Daojun Lv, Ting Li, Yuanyuan Zhang Source: https://www.frontiersin.org/research-topics/77424/cuproptosis-in-cancer-mechanisms-microenvironment-and-therapeutic-exploitation