Dual organelle targeting type I/II photosensitizer triggers ferroptosis-like/apoptosis for photodynamic immunotherapy.

The clinical application of photodynamic therapy (PDT) is substantially hindered by hypoxic tumor microenvironments, limited subcellular targeting capabilities, and suboptimal activation of cell death mechanisms. To overcome these challenges, this study reports a donor-acceptor-π-acceptor (D-A-π-A1) structured photosensitizer (TBTVP) exhibiting dual targeting of cellular membranes and mitochondria to induce ferroptosis-like and apoptotic cell death in cancer cells. Upon exposure to white light irradiation, TBTVP efficiently generates reactive oxygen species (ROS), including singlet oxygen, superoxide anion, and hydroxyl radicals, via both type-I and type-II PDT pathways. Notably, TBTVP selectively accumulates in the membrane and mitochondria. The photosensitized TBTVP depletes glutathione (GSH), disrupts cellular redox homeostasis, compromises membrane integrity, induces mitochondrial dysfunction, and elevates lipid peroxide levels, collectively triggering apoptosis and ferroptosis. Moreover, ROS generated through photoactivation elicit robust immunogenic cell death (ICD), enhance dendritic cell maturation, and promote infiltration of cytotoxic T lymphocytes. These findings provide a promising framework for the development of type I/II photosensitizers in photodynamic immunotherapy for tumors.