All forms of cancer therapy — including immunotherapy, chemotherapy and radiotherapy — rely to some extent on the ability of dying cancer cells to induce an antitumour immune response. However, different cell death modalities have different abilities to activate the immune system. Whereas apoptosis is typically considered immunologically ‘silent’ owing to the maintenance of plasma membrane integrity, lytic forms of cell death such as necroptosis are typically immunogenic owing to the release of immunostimulatory damage-associated molecular patterns (DAMPs) such as HMGB1. Ferroptosis, although lytic in nature, has also been shown to have immunosuppressive effects through the death of immune cells and release of immunosuppressive mediators such as prostaglandin E2 (PGE2). Liu et al. now identify GPX4 as an additional immunosuppressive DAMP, released uniquely by ferroptotic cells, that inhibits dendritic cell (DC) maturation and thus activation of an antitumour response.
To identify potential immune regulators unique to ferroptosis that might account for its reduced immunogenicity, Liu et al. focused on GPX4 and AIFM2, which are key endogenous suppressors of ferroptosis. They showed by various means that 60 human cancer cell lines release GPX4 extracellulary while undergoing ferroptosis but not other forms of cell death. A monoclonal antibody to GPX4 or Gpx4 deletion enhanced the vaccine efficacy of ferroptotic cells but not other dying cells, whereas local injection of GPX4 at the vaccination site reduced the immunogenicity of all forms of cell death.