Stimuli-responsive ferroptosis for cancer therapy

Ferroptosis, an iron-dependent programmed cell death mechanism, is regulated by distinct molecular pathways of lipid peroxidation caused by intracellular iron supplementation and glutathione (GSH) synthesis inhibition. It has attracted a great deal of attention as a viable alternative to typical apoptosis-based cancer therapy that exhibits drug resistance. For efficient therapeutic utilization of such a unique and desirable mechanism, precise control using various stimuli to activate the administered nanocarriers is essential. Specific conditions in the tumor microenvironment (e.g., acidic pH, high level of ROS and GSH, hypoxia, etc.) can be exploited as endogenous stimuli to ensure high specificity of the tumor site. Maximized spatiotemporal controllability can be assured by utilizing external energy sources (e.g., magnetic fields, ultrasound, microwaves, light, etc.) as exogenous stimuli that can provide on-demand remote controllability for customized deep tumor therapy with a low inter-patient variation. Strikingly, the utilization of dual endogenous and/or exogenous stimuli provides a new direction for efficient cancer therapy. This review highlights recent advances in the utilization of various endogenous and exogenous stimuli to activate the reactions of nanocarriers for ferroptosis-based cancer therapy that can inspire the field of cancer therapy, particularly for the treatment of intractable tumors.