Cancer therapy in the necroptosis era

Necroptosis is a caspase-independent form of regulated cell death executed by the receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). Recently, necroptosis-based cancer therapy has been proposed to be a novel strategy for antitumor treatment. However, a big controversy exists on whether this type of therapy is feasible or just a conceptual model. Proponents believe that because necroptosis and apoptosis use distinct molecular pathways, triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. This hypothesis has been preliminarily validated by recent studies. However, some skeptics doubt this strategy because of the intrinsic or acquired defects of necroptotic machinery observed in many cancer cells. Moreover, two other concerns are whether or not necroptosis inducers are selective in killing cancer cells without disturbing the normal cells and whether it will lead to inflammatory diseases. In this review, we summarize current studies surrounding this controversy on necroptosis-based antitumor research and discuss the advantages, potential issues, and countermeasures of this novel therapy.