Beyond antibody fucosylation: α-(1,6)-fucosyltransferase (Fut8) as a potential new therapeutic target for cancer immunotherapy

Abstract

AbstractAberrant post-translational glycosylation is a well-established hallmark of cancer. Altered core fucosylation mediated by α-(1,6)-fucosyltransferase (Fut8) is one of the key changes in tumor glycan patterns that contributes to neoplastic transformation, tumor metastasis, and immune evasion. Increased Fut8 expression and activity are associated with many types of human cancers, including lung, breast, melanoma, liver, colorectal, ovarian, prostate, thyroid, and pancreatic cancer. In animal models, inhibition of Fut8 activity by gene knockout, RNA interference, and small analogue inhibitors led to reduced tumor growth/metastasis, downregulation of immune checkpoint molecules PD-1, PD-L1/2, and B7-H3, and reversal of the suppressive state of tumor microenvironment. Although the biologics field has long benefited tremendously from using FUT8−/− Chinese hamster ovary cells to manufacture IgGs with greatly enhanced effector function of antibody-dependent cellular cytotoxicity for therapy, it is only in recent years that the roles of Fut8 itself in cancer biology have been studied. Here, we summarize the pro-oncogenic mechanisms involved in cancer development that are regulated by Fut8-mediated core fucosylation, and call for more research in this area where modifying the activity of this sole enzyme responsible for core fucosylation could potentially bring rewarding surprises in fighting cancer, infections, and other immune-related diseases.