Cuproptosis and anti-tumor immunity: bidirectional regulation, controversies, and translational prospects

Abstract

Cuproptosis is a copper-dependent form of regulated cell death driven by copper binding to lipoylated tricarboxylic acid (TCA) cycle proteins. This interaction triggers aberrant protein aggregation, Fe-S cluster protein degradation, and mitochondrial proteotoxic stress, and its unique metabolic dependency distinguishes cuproptosis from apoptosis and ferroptosis. This review examines the bidirectional regulation between cuproptosis and anti-tumor immunity. Cuproptosis can promote dendritic cell maturation and CD8+ T cell-mediated immunity through immunogenic cell death (ICD), damage-associated molecular pattern release, and cGAS-STING pathway activation. Activated CD8+ T cells may in turn enhance tumor cell cuproptosis sensitivity via IFN-γ-STAT1-IRF1-driven FDX1 upregulation, forming a positive feedback loop. Conversely, direct copper toxicity toward T cells and NK cells, spatial heterogeneity of intratumoral copper distribution, and potential immunosuppressive cytokine release may counterbalance these immunostimulatory effects. We outline core controversies regarding the universality of cuproptosis immunogenicity, the immune activation window of copper ions, and the clinical utility of cuproptosis biomarkers. Translational strategies including copper ionophore-immunotherapy combinations, copper-based nano-delivery systems, and copper metabolism-based patient stratification are discussed. The cuproptosis-immunity intersection remains at an early stage; key mechanistic findings require independent validation before clinical translation.