Enhanced ferroptosis in triple-negative cancer cells achieved by a type-I cell membrane-targeted tetrabenzophenazine photosensitizer

Triggering ferroptosis emerges as a promising anticancer therapeutic strategy. Photodynamic therapy based on cell membrane-targeted agents presents a chance to facilitate ferroptosis. However, there have been limited reports on this topic. In this study, we introduced a type-I cell membrane-targeted photosensitizer capable of inducing ferroptosis (FQ2). The study demonstrated that FQ2 was located on cell membrane, and the FQ2-mediated PDT could promote ferroptosis, which was attributed to GSH depletion, NADH oxidation, and GPX4 downregulation, ultimately causing lipid peroxidation (LPO) accumulation. Moreover, FQ2 was capable to induce apoptosis, as well as immunogenic cell death (ICD) upon irradiation. Finally, FQ2 exhibited good anticancer activity in vivo using a 4T1 tumor-bearing mouse model. Overall, this work provided an example for the development of cell membrane-targeted ferroptosis inducers.