Targeting of STEAP3 by a selenium D–π–A photosensitizer that activates ferroptosis

Resistance to apoptosis limits the efficacy of many cancer therapies. Photodynamic therapy (PDT), with its spatial precision, offers a promising strategy by engaging nonapoptotic cell death pathways, such as ferroptosis. However, the direct molecular targets of most photosensitizers remain undefined. Here, we introduce a class of selenium-containing D–π–A photosensitizers (PDSe-1 to PDSe-11) and identify PDSe-8 as a lead system with advantageous photophysical properties and potent, hypoxia-tolerant phototoxicity (IC 50 = 53 nM). PDSe-8 elicits a concentration-dependent switching of cell death programs. Low doses trigger apoptosis through p38 mitogen-activated protein kinase (MAPK) signaling, whereas higher doses activate ferroptosis. Competitive chemoproteomics reveals the metalloreductase STEAP3 as a direct molecular target of light-activated PDSe-8 underlying this switch. Upon photoirradiation, PDSe-8 photodegrades STEAP3 in glioblastoma cells, which in turn activates p53, impairs the SLC7A11–GPX4 antioxidant axis, and drives lethal lipid peroxidation, ultimately leading to ferroptotic cell death. This mode of action results in potent antitumor efficacy against U87MG glioblastoma both in vitro and in vivo. This work establishes STEAP3 as a key molecular target for photodynamic therapy and proposes a mechanistically defined selenium photosensitizer that overcomes cancer apoptosis resistance by inducing ferroptosis.