An ER-Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non-Small-Cell Lung Cancer

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti-tumor immunity. An iridium(III) complex (Ir1), containing an N,N-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD inducer for non-small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage-associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1-treated dying cells elicited an antitumor CD8⁺ T cell response and Foxp3⁺ T cell depletion, which eventually resulted in long-acting anti-tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir-based complex that is capable of developing an immunomodulatory response by immunogenic cell death.