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 in vitro and in vivo, 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 in vitro 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 in vitro and in vivo. Complex 2G, with its high phagocytosis
rates and low necrosis rates, was recognized as a bona fide ICD inducer, demonstrating a remarkably long-lasting immune response
in vaccinated mice. In contrast, complex 1C, 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 in vivo administration. Overall, this study offers a framework
for predicting ICD effects in vivo for structurally
similar Au(III) complexes, with the potential for extension to other
series of metal complexes.