A novel FTO-targeting nanodrug induces disulfidptosis and ameliorates the suppressive tumor immune environment to treat uveal melanoma.

Uveal melanoma (UM) is the most prevalent primary ocular malignancy in adults, with high lethality and limited effective treatment options. Despite identified driver mutations in GNAQ, GNA11, and BAP1, therapeutic advancements have been minimal. This study highlights the pivotal role of N6-methyladenosine (mA) modifications in UM pathogenesis and progression, focusing on the demethylase FTO as a therapeutic target. Elevated FTO expression in UM tissues correlates with decreased mA levels, increased aggressiveness, and poor prognosis. The FTO inhibitor meclofenamic acid (MA) restored mA levels, upregulated SLC7A11, and induced disulfidptosis, a unique form of cell death triggered by GSH depletion and NADPH consumption. To address MA's limitations in bioavailability and tumor targeting, we developed an MA-loaded nucleic acid nanodrug (SNAMA). SNAMA demonstrated effective tumor growth inhibition in orthotopic and metastatic UM models through GSH-responsive release and mA-mediated disulfidptosis activation. Incorporating a PD-L1 aptamer into SNAMA further improved tumor targeting and immune modulation, enhancing therapeutic efficacy. This study identifies FTO as a critical target for UM therapy and introduces SNAMA-apt as a promising nanodrug. The findings offer a foundation for mA-targeted approaches in UM and other malignancies, addressing bioavailability, targeting, and immune evasion challenges.