Lysosome-Targeted Iridium(III) Photosensitizers Activate the Mitophagy−Ferroptosis Axis to Boost Two-Photon Photoimmunotherapy Against Hypoxic Cisplatin-Resistant Tumors

Abstract Hypoxia and immunosuppression limit photodynamic therapy (PDT) in treatment-resistant solid tumors. We developed structure-guided, lysosome-targeted Ir(III) photosensitizers and identified a symmetric, π-conjugation-extended dinuclear complex with 810 nm two-photon activation, high singlet-oxygen quantum yield, low dark cytotoxicity, and sustained type-I reactive oxygen species generation under hypoxia. Photoactivation triggered lysosomal membrane permeabilization, cathepsin B release, Ca(II) dysregulation, mitochondrial depolarization, and PINK1-associated mitophagy. This lysosome-to-mitochondria stress relay depleted GSH, inactivated GPX4, increased Fe(II) and lipid peroxidation, and sensitized cisplatin-resistant lung cancer cells to ferroptosis. In a sequential contralateral CMT167 rechallenge model, local treatment suppressed primary tumor growth and delayed the growth of a subsequently implanted, non-irradiated contralateral tumor, accompanied by broad remodeling of the tumor immune microenvironment. These findings establish a hypoxia-tolerant dinuclear photosensitizer that couples two-photon PDT to ferroptosis and systemic antitumor immune activation.