Bioorthogonally Dissociative Rhenium(I) Polypyridine-based Photosensitizers for the Controlled Induction of Immunogenic Cell Death

Cancer immunotherapy offers a promising approach for tumor eradication and prevention of recurrence by enhancing the host immune response. However, challenges such as tumor immunosuppression and off-target toxicity hinder its clinical application. In this study, we designed and synthesized rhenium(I) polypyridine complexes modified with a tetrazine-functionalized carbamate linker as bioorthogonally dissociative photosensitizers for the controlled induction of immunogenic cell death (ICD). These complexes remained inactive under normal conditions, exhibiting low emission intensities and singlet oxygen (1O2) generation efficiencies. However, they were activated upon bioorthogonal dissociation with trans-cyclooct-4-enol (TCO-OH), releasing highly (photo)cytotoxic rhenium(I) aminomethylpyridine derivatives. Notably, the poly(ethylene glycol)-modified complex was specifically localized in the lysosomes and displayed substantially enhanced emission and 1O2 generation upon bioorthogonal activation. Light irradiation of the activated complex induced lysosomal dysfunction, autophagy suppression, and robust ICD, effectively promoting tumor cell death and immune stimulation. This approach highlights the potential of bioorthogonally activatable rhenium(I) polypyridine complexes as innovative photoimmunotherapeutic agents, enabling tumor-specific activation with minimal side effects and potent anticancer immunity.