This research identifies GPX4 as a critical immunosuppressive factor released during ferroptosis, a specific type of iron-dependent cell death. While many forms of cell death trigger immune responses, ferroptotic cells often fail to activate robust defenses because extracellular GPX4 binds to the ZP3 receptor on dendritic cells. This interaction triggers a cAMP-PRKA signaling pathway that inhibits glycolysis, thereby preventing the proper maturation and activation of these vital immune cells. Experiments demonstrate that blocking the GPX4-ZP3 axis can restore the effectiveness of anti-tumor vaccines and improve the results of cancer therapies. High levels of ZP3 expression are further linked to reduced survival and limited T-cell infiltration across various human cancers. Ultimately, the study highlights how targeting this specific molecular interaction could enhance antitumor immunity and clinical outcomes.

References:

• Liu J, Cai X, Lin J, et al. Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors[J]. Cell, 2026.