Photodynamic Therapy in Cancer: Mechanisms, Photosensitizer Technology, Vitamin Modulation, and Rational Combination Design

Photodynamic therapy (PDT) is a minimally invasive anticancer modality based on the interaction of a photosensitizer, light of an appropriate wavelength, and molecular oxygen, resulting in reactive oxygen species (ROS)-mediated tumor injury. This review discusses PDT as a mechanism-dependent therapeutic platform and evaluates how photosensitizers, vitamin A, vitamin D, nanotechnology, and combination strategies may influence its efficacy. The article synthesizes mechanistic and translational evidence concerning photosensitizer activation, ROS generation, tumor cell death, vascular shutdown, immunogenic cell death, and clinically relevant PDT applications. Particular attention is given to the divergent roles of vitamin A and vitamin D. Mechanistic and limited experimental evidence indicates that the effects of vitamin A-related compounds on PDT are heterogeneous and context-dependent. Selected compounds may attenuate PDT through antioxidant or cytoprotective mechanisms, whereas enhancement has also been reported for specific retinoid–photosensitizer combinations; however, clinical evidence remains limited. In contrast, vitamin D may enhance ALA/MAL-PDT by increasing intracellular protoporphyrin IX accumulation through modulation of the heme biosynthetic pathway, especially in non-melanoma skin cancer contexts. Nanocarriers, targeted photosensitizers, oxygen-modulating platforms, chemotherapy, and immunotherapy may further improve PDT when selected according to mechanistic compatibility. Overall, PDT combination design should be guided by whether adjunctive agents support or undermine photosensitizer accumulation, oxygen availability, ROS-mediated cytotoxicity, and immune activation.