Necroptotic cell death in anti-cancer therapy

Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.