Posted by Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.
This review refers to the work of Cheng et al. who successfully developed an injectable hydrogel, Gel@WA-cRGD, that combines the induction of ferroptosis and immunomodulation effects [2]. The hydrogel was created through Ca2+-mediated cross-linking of natural sodium alginate, incorporating crgd-modified redox-responsive Withaferin prodrugs (WA-cRGD) and programmed cell death ligand 1 antibody (aPD-L1) for targeted tumor treatment. Following injection into postoperative trauma cavities, the hydrogels degrade in a microenvironment-responsive manner, releasing β-cyclodextrin (β-CD) and aPD-L1 to the trauma margins. These components are selectively taken up by tumor cells and activated by excess GSH in the cytoplasm, leading to WA-induced ferroptosis and the release of tumor-derived immune substances for recognition and activation of surrounding antigen-presenting cells (APCs). Additionally, aPD-L1 inhibits the PD-1/PD-L1 interaction between tumor and immune cells, reversing the immunosuppressive tumor microenvironment (TME). Gel@WA-cRGD shows promise for postoperative treatment of resected solid tumors to prevent primary tumor recurrence and suppress distal tumors.
[1] Luo Y, Bai XY, Zhang L, Hu QQ, Zhang N, Cheng JZ, Hou MZ, Liu XL. Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches. Drug Des Devel Ther. 2024;18:2485-2529
https://doi.org/10.2147/DDDT.S472178
[2] Cheng Z, Xue C, Liu M, et al. Injectable microenvironment-responsive hydrogels with redox-activatable supramolecular prodrugs mediate ferroptosis-immunotherapy for postoperative tumor treatment. Acta Biomater. 2023;169:289–305. https://doi.org/10.1016/j.actbio.2023.08.002