Cell death: immunogenic potential of cuproptosis in cancer

Abstract

Recent data published in Cell demonstrate that a Cu 2+ -dependent form of regulated cell death (RCD) commonly known as cuproptosis is immunogenic, resulting in the emission of damage-associated molecular patterns (DAMPs) by malignant cells and the initiation of an adaptive anticancer immune response that not only ampli fi es cuproptosis induction, but also can be potentiated with immune checkpoint inhibitors (ICIs). 1 The ability of a given RCD modality to elicit antigen-speci fi c tumor-targeting immune responses associated with an effector phase and immunological memory – hence qualifying as bona fi de immunogenic cell death (ICD) – depends on several variables. 2 Speci fi cally, for dying neoplastic cells to elicit adaptive anticancer immunity, they must: (1) express antigens that are not protected by central tolerance; (2) release multiple DAMPs in a temporally and spatially de fi ned manner during their demise, and (3) undergo RCD within an immunologically permissive tumor microenvironment (TME). 2 Importantly, RCD-associated DAMP release is profoundly in fl u-enced by the biochemical events that precede, drive and accompany cell death. Thus, while necroptosis, which is executed by mixed lineage kinase domain like pseudokinase (MLKL)- mediated plasma membrane permeabilization, represents a highly immunogenic RCD form, 2 apoptosis, which is executed by irreversible and widespread mitochondrial outer membrane permeabilization (MOMP) and accompanied by post-mitochondrial caspase activation, generally occurs in an immuno-logically silent or overtly tolerogenic manner. 3 In this context, the immunogenic potential of a Fe 2+ -dependent form of cell death known as ferroptosis remains debated, and may be highly