Abstract

Head and neck cancer, the sixth most prevalent malignancy worldwide, presents significant therapeutic challenges for advanced-stage patients due to multidrug resistance and the severe toxicity associated with traditional chemotherapeutic agents, such as platinum-based drugs. In this study, we designed and synthesized three new iridium(III) metal complexes [Ir(piq) 2 (IPM)]PF 6 (Ir1), [Ir(bzq) 2 (IPM)]PF 6 (Ir2), [Ir(ppy) 2 (IPM)]PF 6 (Ir3) and evaluated their capacity to induce immunogenic cell death (ICD) in head and neck cancer cells and to elucidate the underlying molecular mechanisms. In vitro experiments demonstrated that these complexes were efficiently internalized by SCC7/FADU cells, significantly suppressed cell migration and proliferation and induced G0/G1 phase arrest and apoptosis. Mechanistic investigations revealed that Ir1, Ir2 and Ir3 activated endoplasmic reticulum stress (ERS) through the PERK/eIF2α/ATF4/CHOP pathway, causing excessive reactive oxygen species (ROS) production and mitochondrial depolarization, leading to calcium overload. These events collectively triggered the hallmarks of immunogenic cell death (ICD), including surface-exposed calreticulin (CRT), HMGB1 release, and extracellular ATP secretion. In vivo studies showed that Ir1 (5 mg/kg) significantly inhibited tumor growth in Balb/c nude mice bearing FADU xenografts and in C3H/HeNCrl syngeneic SCC7 models. The same dose of Ir1 shows comparable antitumor efficiency with cisplatin on SCC7 and FADU tumors. Immunofluorescence analysis revealed a marked increase in CD3 + /CD4 + /CD8 + T-cell infiltration and upregulation of apoptotic markers. Acute toxicity testing confirmed a favorable safety profile, with no evidence of organ damage at therapeutic doses. This study provides experimental evidence for the development of novel low-toxicity, immunomodulatory chemotherapeutic agents.