Self-Assembled arachidonic acid Nanomicelles for Radiation-Induced ferroptosis to enhance tumor Radioimmunotherapy

Abstract

Radiotherapy (RT) induces cancer cell death primarily through apoptosis, a non-inflammatory process that triggers a limited antitumor immune response, making it insufficient to prevent tumor metastasis and recurrence. Ferroptosis is a form of cell death caused by the peroxidation of phospholipids (PLs) containing polyunsaturated fatty acid (PUFA) in the cell membrane. It has been reported that RT can induce ferroptosis, but the low PUFA content in tumors limits the ability of radiation to effectively induce ferroptosis. Herein, we designed a self-assembled nanomicelle (ADM) to deliver arachidonic acid (AA, a type of PUFA) to enhance radiation-induced ferroptosis. Radiation can upregulate acyl-CoA synthetase long chain family member 4 (ACSL4), which converts the abundant AA taken up by cancer cells into AA-PLs and incorporates them into cell membrane. More importantly, reactive oxygen species (ROS) generated by RT promote the peroxidation of PLs containing high levels of PUFA in the cell membrane, thereby inducing ferroptosis and subsequently triggering an effective antitumor immune response. Moreover, encapsulating the Toll-like receptor agonist resiquimod in ADM further potentiates systemic antitumor immunity, significantly inhibiting lung metastasis of 4 T1 breast cancer and preventing tumor rechallenge. Our work presents a new strategy to enhance RT-induced ferroptosis by developing a nanoplatform capable of delivering PUFA.