Mitochondria-specific GPX4 inhibition enhances ferroptosis and antitumor immunity.

Ferroptosis is gaining attention as a potential cancer immunotherapy strategy, as it can stimulate antitumor responses by enhancing dendritic cell (DC) activation and the infiltration of cytotoxic T cells (CTLs). However, cancer cells often develop resistance to ferroptosis, reducing the effectiveness of existing treatments. This study demonstrates a novel mitochondria-targeted ferroptosis inducer, designated mitoFePDA@R, which is engineered to achieve a "closed-loop" cancer immunotherapy strategy of ferroptosis induction, antitumor immune activation, and ferroptosis enhancement. In this strategy, mitoFePDA@R is designed to release Fe and the mitoGPX4 inhibitor RSL3 within tumor mitochondria, thereby effectively inducing ferroptosis and activating strong antitumor immune responses. Additionally, interferon γ (IFN-γ) released from CTLs inhibits GSH synthesis, which further enhances the ferroptosis sensitivity of tumor cells to form a "closed-loop" strategy. In vitro studies indicated that mitoFePDA@R induced strong ferroptosis in tumor cells by accumulating lipid peroxides (LPO) in mitochondria (which lacks mitochondria targeting). Animal studies confirmed that mitoFePDA@R effectively triggered ferroptosis and activated subsequent antitumor immune responses, leading to significant tumor growth inhibition. This provides a viable and effective strategy for ferroptosis-associated cancer immunotherapy.