Harnessing Immunogenic PANoptosis With Iridium(III) Biradical Photosensitizers for Melanoma Photoimmunotherapy.

Publication date: Jul 08, 2026

The efficacy of photodynamic therapy (PDT) is fundamentally constrained by an intrinsic photophysical trade-off between its two ROS-generating mechanisms. Type I pathways require a strongly reducing excited state to drive electron transfer, whereas type II pathways demand a long-lived triplet state to enable efficient energy transfer to molecular oxygen. Since both originate from the same triplet manifold, optimizing one property inevitably compromises the other, limiting the oxidative potency and broad applicability of conventional photosensitizers within the heterogeneous tumor microenvironment. To overcome this limitation, in this study, the design, synthesis, and biological evaluation of a cyclometalated iridium(III) photoswitchable complex is reported, engineered to undergo photo-induced intramolecular homolytic bond cleavage to generate a transient biradical intermediate. The resulting open-shell species simultaneously consist of a strongly reducing radical intermediate and a quinoid-stabilized long-lived triplet excited state, concurrently activating type I electron-transfer and type II energy-transfer pathways to produce in tandem superoxide, hydroxyl radicals, and singlet oxygen. This synergistic dual-pathway oxidative stress triggers PANoptosis, a coordinated cell-death program concurrently engaging apoptotic, necroptotic, and pyroptotic machinery, and elicits a robust systemic antitumor immune response, establishing intramolecular biradical generation as a compelling molecular design principle for next-generation photodynamic cancer immunotherapy.

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