Leveraging Immunogenic Cell Death to Enhance the Immune Response against Malignant Pleural Mesothelioma Tumors

Although various metal-based compounds have exhibited excellent immunogenic cell death (ICD)-inducing properties both <i>in vitro</i> and <i>in vivo,</i> the majority of these compounds have been discovered serendipitously. In this work, we have successfully synthesized and characterized 35 cyclometalated Au(III) complexes containing dithiocarbamate ligands, with 25 of these complexes being previously unreported. Their ability to induce phagocytosis <i>in vitro</i> against immunologically "cold" malignant pleural mesothelioma (MPM) cells was strongly dependent on the cyclometalated scaffold and the overall lipophilicity of the complexes. We elucidated the role of cell death mechanisms in the observed ICD effects and identified correlations between the ability of the complexes to induce necrotic cell death and ICD, both <i>in vitro</i> and <i>in vivo</i>. Complex <b>2G</b>, with its high phagocytosis rates and low necrosis rates, was recognized as a <i>bona fide</i> ICD inducer, demonstrating a remarkably long-lasting immune response in vaccinated mice. In contrast, complex <b>1C</b>, characterized by high phagocytosis rates and high necrosis rates, failed to elicit a sustained immune response upon following vaccination; however, it triggered selective activation of calreticulin in tumors upon direct <i>in vivo</i> administration. Overall, this study offers a framework for predicting ICD effects <i>in vivo</i> for structurally similar Au(III) complexes, with the potential for extension to other series of metal complexes.