Multi-Ion Channel Nanomedicines Targeting Zinc Transporter 1/ATPase Copper Transporters Disrupt Copper/Iron Homeostasis to Enhance Tumor Immunotherapy

Intracellular ion homeostasis is essential for cellular function; tumor cells remodel ion networks to sustain malignant proliferation. Targeting ion homeostasis represents a promising anticancer strategy. Cuproptosis and ferroptosis, emerging programmed cell death modalities, exploit tumor-specific ionic vulnerabilities but are constrained by mechanisms including ATPase copper transporter (ATP7A)-mediated Cu2+ efflux and the solute carrier family 7, member 11 (SLC7A11/xCT)-driven antioxidant axis. We developed an ion-mediated immunotherapeutic nanoplatform (CCZSM) that disrupts Cu2+ and Fe2+ metabolism while activating antitumor immunity. Zn2+ enhances zinc transporter 1 (ZNT1) expression to increase Cu2+ influx; concurrent ATP7A silencing inhibits Cu2+ efflux, inducing cuproptosis. Mitochondrial Fe2+ release combined with Co2+-induced free Fe2+ generates an “Fe2+ storm” that, alongside Cu2+-mediated disruption of cysteine (Cys) metabolism, compromises antioxidant defenses and triggers ferroptosis. This ionic dysregulation induces tumor cell death and promotes release of damage-associated molecular patterns (DAMPs) and mitochondrial DNA (mtDNA), activating immunogenic cell death (ICD) and the cGAS-STING pathway. Resultant dendritic cell (DC) maturation and T-cell activation link ion metabolic interference to systemic immune responses. This study establishes a multi-ion metabolic intervention strategy, advancing tumor immunotherapy paradigms.