Fucoidan-Copper Nanoparticles to Potentiate Synergistic Cancer Cell Cuproptosis and Immunotherapy

Cuproptosis, a newly characterized form of regulated cell death initiated by copper binding to lipoylated components of the tricarboxylic acid cycle, presents a promising target for cancer therapy. Here, we report the development of fucoidan-copper nanoparticles (Fu-Cu) that exploit this mechanism to selectively induce cytotoxicity in HuH-7 liver cancer cells. The Fu-Cu was synthesized using fucoidan, a sulfated polysaccharide with inherent anticancer properties, as a natural nanocarrier for copper ions. Characterization confirmed successful copper incorporation and the formation of stable nanoparticles. Fu-Cu treatment enhanced intracellular copper levels and oxidative stress, triggering cuproptosis mediated by mitochondrial carrier homolog 2. Knockout of ferredoxin 1 in HuH-7 cells mitigated the cytotoxic effects, underscoring its critical role in copper-induced cell death. In vivo studies using a subcutaneous tumor model in BALB/c nude mice demonstrated that Fu-Cu effectively inhibited tumor growth and stimulated antitumor immunity, evidenced by increased infiltration of T cells, natural killer cells, and macrophages within the tumor microenvironment. These findings highlight Fu-Cu as a novel therapeutic strategy for HCC, leveraging the mechanism of cuproptosis and immune activation to suppress tumor progression.