Advances in organelle-targeted photosensitizer-mediated pyroptosis for photodynamic tumor therapy: overcoming immunological limitations

While photodynamic therapy (PDT) shows promise for tumor treatment, its efficacy is often constrained by the immunosuppressive tumor microenvironment. Pyroptosis, a Gasdermin-mediated inflammatory programmed cell death, augments PDT by releasing inflammatory cytokines and damage-associated molecular patterns that trigger robust antitumor immunity. This review systematically outlines the fundamental principles of PDT and critically analyzes existing immunological limitations in tumor treatment, highlighting the immunostimulatory mechanisms of pyroptosis in overcoming these specific therapeutic barriers. In addition, we summarize the rational design principles and recent advances in organelle-targeted photosensitizers-including those targeted to the plasma membrane, mitochondria, lysosomes, Golgi apparatus, and endoplasmic reticulum-for the effective induction of pyroptosis. We further discuss the persisting challenges associated with employing organelle-targeted photosensitizer-induced pyroptosis in tumor therapy. This review provides a strategic framework and future perspectives for developing next-generation precision photo-immunotherapies that harness pyroptosis-PDT synergy.