An Avalanche Effect Nanomodulator Triggers Cascade Ferroptosis/Cuproptosis for Immunosuppressive Microenvironment Remodeling

ABSTRACT

The tumor immunosuppressive microenvironment severely impedes the efficacy of immunotherapy. An avalanche effect nanomodulator, L‐Arginine/lificiguat@Copper‐hollow Prussian blue@Calcium phosphate nanoparticles, activates immunotherapy and remodels the immunosuppressive microenvironment through cascade‐triggered ferroptosis and cuproptosis. Within the tumor microacidic environment, calcium ions released by the nanomodulator induce mitochondrial calcium overload and membrane potential collapse. Concurrently, the nanomodulator alleviates tumor hypoxia through synergistic nitric oxide production and hypoxia‐inducible factor‐1α signaling pathway inhibition. Under 808 nm laser irradiation, the photothermal effect of the nanomodulator further promotes nitric oxide and iron/copper ions release. Iron and copper ions generate abundant reactive oxygen species through multiple enzyme activities, a process that synergizes with nitric oxide to form a reactive oxygen species/reactive nitrogen species storm, which intensifies lipid peroxidation and glutathione depletion, ultimately inducing ferroptosis and cuproptosis. The two immunogenic cell death pathways of ferroptosis and cuproptosis significantly promote dendritic cell maturation and cytotoxic T lymphocyte infiltration, transforming cold tumors into hot tumors. The nanomodulator effectively remodels the immunosuppressive microenvironment to establish robust systemic antitumor immune memory, thereby inhibiting primary tumor growth and distant metastasis, offering a novel strategy for tumor immunotherapy.