Interconnected death: crosstalk among ferroptosis, cuproptosis, and pyroptosis in cancer

Ferroptosis, cuproptosis, and pyroptosis are distinct forms of programmed cell death (PCD) that are increasingly recognized as interconnected regulators of tumor progression, metabolic adaptation, and therapeutic response beyond classical apoptosis. While research into individual pathways has expanded rapidly, a cohesive mechanistic framework integrating their crosstalk remains incompletely understood. In this review, we propose an “interconnected death” framework in which the biological effects of these death modalities are jointly determined by shared stress inputs, the identity of the dying cell, the spatial and temporal pattern of the death event, and the responses of surrounding cells. We summarize their core mechanisms and examine their crosstalk through mitochondrial metabolism, glutathione and redox homeostasis, lipid peroxidation, autophagy, and immune-inflammatory signaling. We further discuss how these interactions influence tumor initiation, clonal selection, metastasis, antitumor immunity, and therapeutic resistance, with particular attention to their cell-type-specific consequences within the tumor microenvironment. The ability of cancer cells to exploit this regulatory plasticity to promote immune evasion and therapy resistance underscores the need to develop multimodal therapeutic strategies. We evaluate pathway-selective inducers, rational combination therapies, and targeted delivery approaches, while also considering the major challenges that currently limit their clinical translation. Together, these insights provide a conceptual basis for the development of precision therapeutic approaches.