PDTAC: Targeted photodegradation of GPX4 triggers Ferroptosis and potent antitumor immunity

Targeted degradation of proteins, especially those regarded as ‘undruggable’, attracts wide attention to develop novel potential therapeutic strategy. GPX4, a key enzyme regulating ferroptosis, is such a target whose inhibition is currently limited to molecules acting through covalently binding. Here, we have developed a targeted photolysis approach to achieve the efficiently degradation of GPX4. The Photo-Degradation TArgeting Chimeras (PDTACs) were synthesized by conjugating a clinically approved photosensitizer Verteporfin to GPX4-targeting peptides. Although the ligands themselves exhibit neither inhibitory nor degrading activity towards GPX4, these chimeras degraded selectively the target protein in living cells upon red-light irradiation. In contrast to the application of Verteporfin alone, the targeted photolysis of GPX4 resulted in dominant ferroptotic cell death in malignant cancer cells of different origins. Moreover, the dying cells resulted from our chimeras exhibited potent immunogenicity in vitro, and elicited more efficiently anti-tumor immunity in vivo in comparison with those dying from Verteporfin. Our approach therefore provides a novel method to dysfunction GPX4 based on noncovalent binding and specifically trigger immunogenic ferroptosis, which may boost the development of triggering ferroptosis as a potential strategy in cancer immunotherapy.