Photodynamic therapy mediates antitumor effects through multiple non‑apoptotic cell death pathways.

Abstract

Photodynamic therapy (PDT) demonstrates remarkable versatility by activating diverse non-apoptotic cell death pathways, effectively circumventing apoptosis resistance and enhancing tumor eradication. Key mechanisms include autophagic cell death, regulated necrosis-driven immune activation, ferroptosis-mediated oxygen replenishment, pyroptosis-induced immunogenic cell death (ICD), and paraptosis. These pathways collectively highlight PDT's capacity to disrupt tumor survival mechanisms and stimulate systemic anti-tumor immunity. However, several challenges remain, including precise spatiotemporal control of ROS, hypoxia mitigation, and selective photosensitizer delivery. Advances in nanotechnology, hypoxia-responsive agents, and combination therapies (e.g., immune checkpoint inhibitors or chemotherapy) hold promise for overcoming these limitations. In this review, we discuss multiple types of non-apoptotic cell death pathways activated by PDT and the underlying mechanisms of each distinct cell death process. We also review the clinical applications and current challenges of leveraging these pathways to enhance tumor treatment in PDT. Future research should prioritize the development of subcellular-targeted photosensitizers, deeper light-penetration technologies, and biomarker-guided personalized regimens for more precise and effective PDT.