A metal-immuno photosensitizer strategy: Iridium(III)-zidovudine conjugate triggering sequential organelle stress and synergizing with PD-L1 inhibitor in oral squamous cell carcinoma

Insufficiently sustained stress signaling and the low immunogenicity of tumor constrain the efficacy of photodynamic therapy (PDT) in oral squamous cell carcinoma (OSCC). To address this, we developed a light-activated iridium(III)-zidovudine ( IrAZT ) conjugate to trigger sequential organelle stress as a subcellular cascade strategy for OSCC treatment. Upon irradiation, IrAZT translocated from the endoplasmic reticulum (ER) to mitochondria and generated reactive oxygen species (ROS) for potent tumor ablation. This cascade first induced ER stress along with immunogenic cell death (ICD), facilitating the release of tumor antigens and damage-associated molecular patterns (DAMPs) for enhanced tumor immunogenicity. Subsequently, it caused mitochondrial DNA damage, activating the cGAS-STING pathway to drive a potent antitumor immune response. Notably, the treatment adaptively upregulated PD-L1 expression, and its combination with a PD-L1 inhibitor synergistically reprogrammed the immunosuppressive microenvironment in vivo . In all, our study offered a promising avenue for OSCC treatment through a subcellular organelle-targeting cascade strategy and synergizing with immunotherapy, thus providing a novel precision therapeutic strategy for OSCC. • Insufficiently sustained stress signaling and the low immunogenicity of tumor constrain the efficacy of PDT in OSCC. • IrAZT elicited PDT effects through generating both Type I and II ROS. • IrAZT induced sequential organelle stress and ICD. • IrAZT -mediated PDT synergized with PD-L1 immunotherapy for enhanced antitumor immunity.