Metal-based photosensitizers for organelle-targeted photodynamic therapy: From ligand design principles to antitumor immunity

Metal-based photosensitizers should be evaluated not only by the amount and identity of reactive oxygen species (ROS) they generate, but also by whether coordination design positions photochemical injury at a subcellular site that produces a useful immune consequence. This review is therefore organized around two linked frameworks: a coordination design-to-organelle localization map and an organelle damage-to-immunity axis. Within the first framework, we examine how metal identity, ligand electronics, coordination geometry, charge, lipophilicity, and protonation jointly influence excited-state behavior, ROS pathways, and intracellular distribution. Representative ligand series illustrate both the explanatory value and the limits of current structure–activity relationships. Within the second framework, we distinguish intracellular death execution from the recognition of damage signals by immune cells, considering apoptosis, ferroptosis, pyroptosis, antigen presentation, and systemic antitumor responses. We further identify major translational constraints, including incomplete validation of in vivo organelle localization, dark and long-term metal-associated toxicity, hypoxia, clearance, and the limited comparability of existing studies. On this basis, five evidence-graded directions are discussed: AND-gate activation, regulation of Type I/Type II photochemistry, temporal control through chemical transformation, multi-organelle intervention, and artificial intelligence informed by coordination chemistry. Together, these frameworks provide mechanistically grounded criteria for designing and evaluating metal-based photosensitizers that connect coordination chemistry with subcellular photodamage and antitumor immune activation.