Photo-Activated Ferrocene-Iridium(III) Prodrug Induces Immunogenic Cell Death in Melanoma Stem Cells

Cancer stem cells (CSCs) are key contributors to tumor resistance, recurrence, and metastasis. Conventional chemotherapy often fails to target and eradicate CSCs, significantly impairing their therapeutic efficacy. Herein, we design and synthesize a photoactivated ferrocene-iridium(III) complex (Ir-3) to achieve immunotherapy against melanoma cells (including stem cells). In short, Ir-3 effectively targets mitochondria and dissociates under light irradiation to produce a cytotoxic Ir(III) photosensitizer and Fe²⁺ ions. They can generate reactive oxygen species by the Fenton reaction, robustly induce ferroptosis and autophagy, and eventually trigger immunogenic cell death in melanoma cells (including stem cells). Furthermore, under light exposure, Ir-3 effectively inhibits stem cell-related properties and promotes macrophage-mediated phagocytosis of melanoma stem cells. For in vivo studies, Ir-3 is encapsulated in DSPE-PEG 2000 to form tumor-targeting Ir-3@PEG nanoparticles. After photoactivation, Ir-3@PEG can significantly inhibit primary and distant tumors, effectively inhibit the stemness of melanoma stem cells, and induce innate and adaptive immune responses.