Cuproptosis: Bridging targeted therapy and immunotherapy in cancer treatment

Cancer therapy has entered an era dominated by molecularly targeted agents and immune checkpoint inhibitors (ICIs), yet therapeutic resistance and patient heterogeneity remain major barriers to durable benefit. Cuproptosis, a recently identified form of copper-dependent regulated cell death linked to mitochondrial metabolism, has emerged as a potentially relevant therapeutic concept. Distinct from apoptosis and ferroptosis, cuproptosis is triggered by the interaction of copper with lipoylated enzymes in the tricarboxylic acid (TCA) cycle, leading to proteotoxic stress and metabolic collapse. Here, we review cuproptosis as a context-dependent metabolic vulnerability and a potential interface between targeted therapy and immunotherapy. We discuss how targeted agents and copper-modulating compounds may, in selected settings, cooperatively enhance cuproptosis-associated stress, and how cuproptosis may contribute to immunogenic cell death (ICD)-like features and tumor immune microenvironment remodeling. We further evaluate the translational relevance of cuproptosis-related gene (CRG) signatures and nanotechnology-enabled delivery platforms, while emphasizing that most current evidence remains preclinical or correlative. Overall, cuproptosis represents a promising but still evolving framework at the intersection of metallobiology, metabolic regulation, and tumor immunity, warranting further mechanistic and translational investigation.