Molecular response of photodynamic therapy in oncology: A comprehensive review

Photodynamic therapy (PDT) is a less invasive phototherapeutic approach that depends on the interaction of three key elements: a photosensitizer (PS), light of a suitable wavelength, and molecular oxygen. Upon photoactivation, the PS produce reactive oxygen species (ROS), particularly singlet oxygen (¹O₂), which trigger localised oxidative stress and initiate a cascade of molecular responses. These responses not only induce direct cytotoxicity but also cause vascular injury, promote inflammatory signaling, activate the immune system, and involve multiple regulated cell death pathways. The severity of the biological PDT response depends on PS chemistry, intracellular localisation, light intensity, fluence rate, oxygen availability, and the molecular environment of the target cells. Accruing evidence from in vitro, in vivo, and clinical studies demonstrates that PDT is not only a local photochemical treatment but also a biologically multifaceted approach for modifying tumour behaviour and the surrounding microenvironment. This review provides an overview of the molecular mechanism of PDT, the modes of cell death induction, and translational evidence supporting its therapeutic significance. We further highlighted the defining features of PDT and discussed current limitations and future perspectives, including improved PS design, targeted delivery, oxygen-modulating strategies, and potential combination therapies with immunotherapy and other modalities. This review uniquely highlights that PDT can simultaneously initiate multiple interconnected regulated pathways, including apoptosis, ferroptosis, pyroptosis, necroptosis, and autophagic cell death, via common oxidative and organelle-specific stress mechanisms. This may elucidate its effectiveness against tumors resistant to therapies that only activate a single pathway.