PlatinER: A Highly Potent Anticancer Platinum(II) Complex that Induces Endoplasmic Reticulum Stress Driven Immunogenic Cell Death

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo‐immunotherapeutic combination regimens through the establishment of a long‐term cancer immunity. None of the clinically used DNA‐binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII‐carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt‐NHC and compared their efficiency in triggering ICD‐related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD‐associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER‐localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. A platinum(II)‐carbene Type II immunogenic cell death (ICD) inducer, PlatinER, promotes phagocytosis by immune cells via release of ICD‐associated DAMPs, including surface exposure of calreticulin and HSP‐90. By comparing its activity against a panel of structurally analogous PtII‐carbene analogues, we determined that PlatinER acts by invoking a partial endoplasmic reticulum (ER) stress response through localised generation of reactive oxygen species in the ER.