Synergistic Antitumor Immunotherapy via Mitochondria Regulation in Macrophages and Tumor Cells by an Iridium Photosensitizer

Mitochondrial targeting has emerged as an attractive method for antitumor treatment. However, most of the mitochondria targeted drugs focused on inhibiting tumor cells, while their potential for activation of immune responses in the tumor microenvironment has rarely been described. In this study, we report a photosensitive iridium complex <b>MitoIrL2</b>, which enabled the simultaneous mitochondrial modulation of macrophages and tumor cells to achieve synergistic antitumor immunity. The adjustment of the mitochondrial respiratory chain, HIF-1α, and the NF-κB pathway in macrophages drove the metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis, converting protumor M2 into the antitumor M1 phenotype. Downregulated expression of immunosuppressive checkpoint SIRPα has also been observed on macrophages. Meanwhile, the mitochondrial targeting <b>MitoIrL2</b> enhanced the immunogenic cell death of tumor cells and reversed the immunosuppressive tumor microenvironment, which activated the systemic immune response and established long-term immune memory <i>in vivo</i>. This work illustrates a promising strategy to simultaneously regulate macrophages toward the antitumor phenotype and enhance immunogenic cell death in tumor cells for synergistic antitumor immunotherapy.