Phenolato Ti IV Complexes as Bifunctional Antitumor Agents: Synergistic Photodynamic Therapy, In Situ Ti III -Mediated Cytotoxicity, and Immune Activation

We present a ferrocene-functionalized phenolato TiIV complex stabilized by dipicolinic acid (Fer-Ti-1) as a nonheavy-metal photosensitizer for photodynamic therapy (PDT), integrating photoactivation with immune modulation. Fer-Ti-1 is highly stable in aqueous solutions, exhibiting strong visible-light absorption from ligand-to-metal and metal-to-metal charge-transfer transitions. Upon 560 nm irradiation, Fer-Ti-1 undergoes in situ transformation to a TiIII bis-dipicolinic acid species, leading to efficient hydroxyl-radical generation and potent photocytotoxicity against multiple tumor cell lines, while remaining nontoxic in the dark and to normal AML12 cells. Detailed uptake and organelle profiling reveal rapid internalization and preferential mitochondrial accumulation, inducing mitochondrial depolarization and dual programmed cell death, predominantly ferroptosis and apoptosis. Photoactivated Fer-Ti-1 also triggers mitochondrial DNA leakage and activates the cGAS-STING pathway, driving immunogenic cell death, dendritic-cell maturation, and enhanced T-cell responses. In Hep G2 xenografts, Fer-Ti-1 plus light achieves strong tumor suppression with favorable safety, establishing a biocompatible Ti-based PDT and immunotherapy platform.