Advances in Targeted Toxin Therapy for Malignant Gliomas: A Narrative Review.

Malignant gliomas remain highly treatment-resistant brain tumors despite surgery and adjuvant therapies. Targeted toxin therapies represent a unique strategy that exploits receptor-mediated cellular internalization to deliver cytotoxic components that result in the irreversible inhibition of protein synthesis independent of DNA damage or cell-cycle status. Advances in molecular profiling, toxin engineering, and delivery development have refined components targeting IL4Rα, IL13Rα2, EGFR/EGFRvIII, uPAR, and the transferrin receptor. Early clinical studies demonstrated biological activity, acceptable safety, and durable responses in subsets of patients, validating the fundamental mechanism of this approach. However, late-phase trials failed to demonstrate a population-level survival benefit, largely due to variability in delivery, receptor heterogeneity, and limitations in trial design rather than insufficient cytotoxic potency. Recent progress has focused on multiple receptor-targeting and delivery systems capable of achieving reliable intratumoral distribution. MRI-guided convection-enhanced delivery, vector-mediated toxin expression, and blood-brain barrier penetrant nanocarriers now enable more precise tumor targeting. Emerging evidence also reveals that toxin-mediated cytotoxicity can enhance antitumor immune responses, supporting their integration with immunotherapy. These advances position targeted toxins as precision cytotoxic compounds whose success depends on coordinated molecular targeting, delivery optimization, and biologically stratified patient selection, establishing a translational pathway for future glioma therapy.