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.