Jian Xiao,Nana Feng,Qiushi Li,Xianghui Cao,Qingqing Huang,Biyu Zhou,Zhenrui Fan,Liping Wei,Yang Liu
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 2+ 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.
Ye Yuan,Chunyu Tian,Qi Wang,Xinyu Qiu,Yufang Wang,Hulin Jiang,Jifu Hao,Yujing He
As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H 2 O 2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG 2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe 2+ , and subsequently the formed iron redox pair (Fe 2+ /Fe 3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.
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