Paraptosis, a new type of cell death that can be applied to cancer treatment.

Paraptosis is a form of non-apoptotic cell death characterized by cytoplasmic vacuolization and swelling of the mitochondria and endoplasmic reticulum (ER). Recent studies have demonstrated that inducing paraptosis in cancer cells can circumvent apoptosis resistance and synergize with other forms of cell death and tumor immunity, providing a novel strategy for anti-tumor therapy. The underlying mechanism of paraptosis involves ER stress triggered by inducers, leading to the swelling of the ER and mitochondria. This subsequently alters the cytoskeleton and disrupts molecular processes, such as calcium (Ca2+) homeostasis, ultimately causing cytoplasmic vacuolization and cell death. Unlike other forms of programmed cell death, paraptosis is caspase-independent and is marked by mitochondrial and ER swelling, along with extensive cytoplasmic vacuolization, without nuclear pyknosis or cell membrane rupture. Various natural compounds, chemical agents, and nanomedicines have been shown to induce paraptosis, which also holds potential in immunotherapy by promoting immunogenic cell death (ICD) and systemic anti-tumor responses. Thus, in cases where cancer cells evade and develop resistance to conventional pro-apoptotic therapies, paraptosis induction offers an alternative therapeutic approach. A comprehensive understanding of the molecular mechanisms underlying paraptosis and its targeted induction may facilitate the development of novel cancer treatments. This paper explores the impact of paraptosis on cancer cells, the mechanisms by which different drugs induce paraptosis, and the potential applications of paraptosis in cancer therapy.