Leveraging tumor cell ferroptosis for colorectal cancer treatment via nanoelicitor-activated tumoricidal immunity

Ferroptosis is an iron- and reactive oxygen species-dependent form of regulated cell death with great clinical translational potential for cancer treatment, however, the efficacy of ferroptosis-elicitable agents is susceptible to many an inhibitory endogenous mediator in vivo. Glutathione peroxidase 4 (GPX4), a central regulator of lipid peroxidation, was found signigicantly up-regulated in colorectal tumors, which inhibits tumor cell ferroptosis. To leverage ferroptosis combating colorectal cancer, here we report a Hypoxia-responsive nanoelicitor (HRNE) for promoting lipid peroxidation and thus facilitating ferroptosis by relieving GPX4-mediated brake. By self-assembling of immune-elicitable polyphenols, Chlorogenic acid (CA) and Mitoxantrone (MIT), with Fe3+ ions, the self-deliverable nanoelicitors were constructed and then cloaked with a hypoxia-responsive hybrid liposomal membrane. In the hypoxic tumor, the liposomal shell discomposed and the nanoelicitor was burst released. Ferroptosis-inducible Fe2+ accompanied with toxic reactive oxygen species was produced via Fenton reaction. An activated tumoricidal immunity was simultaneously co-stimulated by MIT and CA, through which the system xc− to GPX4 pathway was aborted, and the facilitated lipid peroxidation in turn promoted the iron-initiated tumor cell damage. We highlight the nanoelicitor significantly attenuated the GPX4-mediated inhibition of lipid peroxidation by activating a robust tumoricidal immunity and thus synergistically potentiated cancer cell ferroptosis.