Fucoidan-Copper Nanoparticles to Potentiate Cancer Cell Cuproptosis and Tumor Immune Microenvironment Enhancement

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 reported the development of fucoidan-copper nanoparticles (Fu-Cu) that exploit this mechanism to selectively induce cytotoxicity in HuH-7 liver cancer cells. 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. Knockout of ferredoxin 1 in HuH-7 cells mitigated the cytotoxic effects of Fu-Cu, underscoring its critical role in copper-induced cell death. Furthermore, we investigated the toxicity and mechanistic effects of Fu-Cu in Caenorhabditis elegans. In vivo studies using a subcutaneous tumor model in BALB/c nude mice demonstrated that Fu-Cu effectively inhibited tumor growth. Notably, Fu-Cu treatment was associated with enhanced innate immune cell infiltration in the tumor microenvironment, including increased NK-cell and macrophage recruitment, along with elevated peripheral CD19⁺ B-cell frequencies. These findings highlight Fu-Cu as a novel therapeutic strategy for hepatocellular carcinoma, leveraging both cuproptosis induction and tumor immune microenvironment enhancement to suppress tumor progression.