Immunogenic cell death: synergizing ferroptosis and cuproptosis to overcome immunotherapy resistance.

The advent of immune checkpoint inhibitors has fundamentally changed the face of oncology, but the prevalence of primary and acquired resistance has led to the need for the development of novel approaches to remodel the immunosuppressive tumor microenvironment. Central to this challenge is the dichotomy between hot inflamed and cold (immune-excluded) tumors, which is increasingly associated with the immunogenicity of cell death modalities used by therapeutic agents. While apoptosis is largely immunologically silent, regulated cell death pathways driven by the catastrophic failure of mitochondrial metal ion homeostasis, i.e. ferroptosis, and the recently characterized cuproptosis, have emerged as potent drivers of immunogenic cell death. This review represents a comprehensive synthesis of the molecular mechanisms that control these metal-dependent lethal cascades, which includes a detailed account of the biochemical divergence of the iron-dependent Fenton chemistry versus the copper-dependent protein lipoylation and aggregation. We elucidate the role of the mitochondrion as a critical upstream contributor and signal amplifier where bioenergetics, iron-sulfur (Fe-S) cluster stability, and metal toxicity converge to trigger the release of damage-associated molecular patterns such as HMGB1 and ATP. Furthermore, we incorporate the emerging layer of epitranscriptomic regulation, showing how N6-methyladenosine (m6A) modifications influence the spatial architecture of the tumor, the expression of metal transporters and vulnerability genes (e.g. FDX1, SLC7A11) and determine the immune phenotype. By examining the synergistic potential of co-targeting ferroptosis and cuproptosis, we propose a therapeutic framework for overcoming immunotherapy resistance, which may potentially convert the metabolic vulnerabilities of cancer cells into immunological activating signals, hypothesized to drive durable anti-tumor immunity.