Fucosylation of the Fc region plays a critical role in modulating antibody-dependent cellular cytotoxicity (ADCC) through its impact on Fcγ receptor (FcγR) binding. Here, we utilized CRISPR-Cas9 to generate FUT8-knockout (KO) CHO-S cells, effectively abolishing core fucosylation. Additionally, we engineered an anti-nectin-2 antibody with an L235D mutation in the Fc region and compared its binding affinity to FcγRI, FcγRIIA, FcγRIIB, and FcγRIII with the wild-type antibody (L234, L235). The FUT8 KO system was then employed to express both wild-type and L235D-mutated anti-nectin-2 antibodies, further assessing their FcγR binding properties. Our results indicate that the absence of core fucose enhances FcγRIII binding, potentially improving ADCC activity, while the L235D mutation modulates interactions with FcγRs. These findings suggest that engineering Fc fucosylation and point mutations could fine-tune effector functions, offering a novel strategy for optimizing therapeutic antibody design, particularly in nectin-2-overexpressing cancers.