What question did this study set out to answer?

This research aims to explore how targeting copper and iron ion homeostasis can enhance tumor immunotherapy.

April 10, 2026ACS Nano0 citations

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

Key Points

This research aims to explore how targeting copper and iron ion homeostasis can enhance tumor immunotherapy.
Developed a nanomedicine platform (CCZSM) that manipulates ion metabolism.
Increased Cu2+ influx by enhancing zinc transporter 1 expression.
Silenced ATP7A to inhibit Cu2+ efflux, triggering cuproptosis.
Induced Fe2+ storm through Co2+ and mitochondrial Fe2+ release.
Activated immune responses through immunogenic cell death and cGAS-STING pathway.
Ion dysregulation resulted in significant tumor cell death.
Enhanced release of DAMPs and mtDNA activated immune responses.
Promoted dendritic cell maturation and T-cell activation.

Abstract

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.

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