5-Aminolevulinic Acid-Based Radiodynamic Therapy for Malignant Gliomas: A Conceptual Framework for Mitochondria-Centered Mechanisms, Target Cell States and Translational Perspectives.

5-Aminolevulinic acid (5-ALA) is a naturally occurring heme precursor with a favorable safety profile and is widely used for fluorescence-guided resection of malignant gliomas. Exogenous administration of 5-ALA results in the selective intracellular accumulation of protoporphyrin IX (PpIX), predominantly within tumor cell mitochondria, reflecting tumor-specific alterations in cellular metabolism and heme biosynthetic pathways. Historically, the radiosensitizing potential of 5-ALA was considered limited, as 5-ALA itself is not a porphyrin and intracellular PpIX levels are lower than those achieved with classical porphyrin-based agents, such as hematoporphyrin derivatives or porfimer sodium. Recent experimental and translational studies have challenged this view by demonstrating that the interactions between 5-ALA-induced PpIX and ionizing irradiation elicit biologically significant antitumor effects. This emerging concept has been termed radiodynamic therapy (RDT) and represents a therapeutic paradigm distinct from conventional DNA-centered radiosensitization. Accumulating evidence suggests that 5-ALA-based RDT induces mitochondria-centered oxidative stress through both immediate and delayed reactive oxygen species generation, thereby linking metabolic vulnerability to the radiation response. In this review, we summarize the current mechanistic insights into 5-ALA-based RDT, particularly mitochondrial dysfunction and oxidative stress amplification. We also discuss the translational implications and future perspectives for integrating 5-ALA-based RDT into multimodal treatment strategies for malignant gliomas.