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l-Fucose: a dietary sugar with multifaceted potential in the biology and therapy of cancer

Nature Reviews Cancer (2026)Cite this article

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Abstract

Fucosylation, the conjugation of glycoproteins and glycolipids with the dietary sugar l-fucose, can have key functional and regulatory roles across a range of normal biological and developmental processes. Although the full repertoire of fucosylated proteins and their direct influence on signalling and cellular behaviour remains incompletely understood, it is not surprising that deregulated fucosylation has been increasingly associated with disease contexts, particularly cancer. Importantly, fucosylation regulates the biology of immune and other stromal cells, and emerging studies have elucidated how pathological aberrations in fucosylation can deregulate signalling that governs cellular interactions in the tumour microenvironment, thereby influencing tumour progression and therapeutic responses. Accordingly, fucosylated glycoproteins and glycans have been reported to exhibit potential biomarker utility, associating with cancer type and staging. Notably, fucosylation appears to be therapeutically actionable, as simply administering l-fucose orally can suffice to suppress tumour growth and stimulate antitumour immune responses in preclinical models. However, given that the blockade of fucosylation machinery can elicit similar antitumour effects reflects the diversity of cell-intrinsic and cell-extrinsic roles that fucosylation can divergently have across the tumour microenvironment. Here, we review recent glycobiology discoveries that shed light on the complexity of fucosylation, its mechanistic roles in immune and tumour biology, and how it might be strategically leveraged for the treatment of cancer.

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Fig. 1: Fucosylation pathways.
Fig. 2: Fucosylation in immune cell function.
Fig. 3: Therapeutic targeting of fucosylation.

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Acknowledgements

The authors thank H. Kashfi (Lau laboratory) for the critical readings and feedback on this manuscript. This work was supported in part by a Judith Ann Mogan Foundation Graduate Fellowship to A.B. and NCI grants to E.K.L. (R01CA241559 and R21CA286226) and to the Oregon Health & Science University Knight Cancer Institute (P30CA069533).

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  1. These authors contributed equally: Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde.

Authors and Affiliations

  1. Graduate Program in Biomedical Sciences, Oregon Health & Science University, Portland, OR, USA

    Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde & Eric K. Lau

  2. Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde & Eric K. Lau

  3. Cancer Prevention and Control Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde & Eric K. Lau

  4. Cancer Biology Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Amirreza Bitaraf, Maria Camila Jimenez, Chinmayee Kakirde & Eric K. Lau

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Glossary

Adipocytes

Adipose tissue-specialized cells that control the storage and release of free fatty acids throughout the body and are regulated by endocrine regulatory signals.

Adoptive cell transfer

The process of isolating immune cells from a patient (autologous) or donor (allogeneic), which are modified ex vivo, and then re-infused into a patient to treat cancer.

Androgen receptor

(AR). An intracellular receptor that, upon binding to male sex hormones (androgens) including testosterone, can translocate into the nucleus to serve as a transcription factor, thereby regulating cellular responses to androgen.

Click chemistry

A class of modular, high-yield reactions used to attach molecular probes to biomolecules such as proteins, DNA and carbohydrates; often involving azides and alkynes to form carbon-heteroatom bonds designed to be highly selective and to allow for their visualization, tracking and functionalization.

Elastin microfibril interface (EMI) domains

Cysteine-enriched domains located at the N terminus of proteins of the elastin microfibril interface-located protein 1 (EMILIN1) protein family, which are involved in the interaction between elastin and microfibrils in the extracellular matrix.

Epidermal growth factor (EGF)-like repeats

Conserved protein domains, consisting of six conserved cysteine residues, which form three disulfide bonds that stabilize the protein structure.

Fibroblasts

Connective tissue-specialized cells, the predominant functions of which are related to building and remodelling the extracellular matrix.

Galactosylation

The enzymatic process by which a galactose residue is transferred from a sugar nucleotide donor (for example, UDP-galactose) to an acceptor substrate, forming a glycosidic linkage and modifying glycoproteins or glycolipids.

Glycans

Complex carbohydrate molecules composed of n number of monosaccharides connected by glycosidic bonds.

Hydrazide chemistry

A biochemical method using hydrazide (–C(=O)NHNH2) functional groups to react with oxidized glycans (aldehydes) for covalent capture or enrichment of glycoproteins and peptides.

Hydrophilic interaction liquid chromatography

(HILIC). A liquid chromatography mode that uses a polar stationary phase (for example, silica) and a mobile phase with high organic solvent (for example, acetonitrile) to separate hydrophilic and polar analytes.

Lectin

A naturally occurring carbohydrate-binding protein derived mainly from plant sources and can be highly specific for sugar groups.

Lewis antigens

A family of fucosylated oligosaccharide determinants expressed on glycoproteins or glycolipids (typically on type 1 or type 2 lactosamine chains) that are part of the histo-blood group systems and mediate cell surface recognition events including blood-group phenotypes, leukocyte adhesion and pathogen binding.

Macropinocytosis

An endocytic process initiated by invagination of the cell membrane to engulf large soluble extracellular contents into primary endocytic vesicles.

Mannosylation

The enzymatic addition of a mannose residue from a sugar nucleotide donor (for example, guanosine diphosphate (GDP)-mannose) onto an acceptor molecule to form a glycosidic linkage.

Matrix-assisted laser desorption/ionization mass spectrometry imaging

(MALDI-MSI). A technique that uses a mass spectrometer to generate images of the spatial distribution of molecules in a sample, typically a thin tissue section.

Monosaccharide

The simplest sugar structure found in nature (for example, glucose, galactose and fructose); complex structures can be made by glycosidic linkages between monosaccharides to form polysaccharides.

Mucin

A high molecular weight glycoprotein synthesized by epithelial mucosal cells, heavily O-glycosylated with oligosaccharides on serine/threonine residues, that contributes to mucus formation and barrier and adhesive functions.

N-Acetylglucosamine

(GlcNAc). An amide derivative of the monosaccharide glucose and secondary derivative of glucosamine and acetic acid.

N-Glycans

Glycan branches conjugated onto asparagine residues in a peptide or protein, by a N-glycosidic bond.

O-Glycans

Glycans conjugated onto the oxygen of a serine or threonine residue.

Oxidative stress

A physiological or pathological state in which the production of reactive oxygen species exceeds the capacity of antioxidant and repair systems, leading to biomolecular damage.

Sialylation

A post-translational modification in which sialic acid, a type of alpha-keto sugar with a nine-carbon backbone, is added to the terminal ends of glycoprotein and glycolipid chains and has roles in various cellular processes, including cell recognition, immune responses and development.

Sialyl Lewis X

(sLeX). A fucosylated, sialylated tetrasaccharide glycan (Neu5Acα2-3Galβ1-4[Fuc〈1-3]GlcNAc) that serves as a key ligand for the selectin family of cell adhesion molecules (E-selectin, P-selectin and L-selectin), thereby mediating leukocyte rolling and extravasation in inflammation.

Thrombospondin type I repeats

(TSRs). Conserved domains of approximately 60 amino acids found in matrix proteins such as the thrombospondin family of proteins; exhibit a unique 3-stranded fold with a positive charge groove, which may mediate ligand–receptor interactions.

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Bitaraf, A., Jimenez, M.C., Kakirde, C. et al. l-Fucose: a dietary sugar with multifaceted potential in the biology and therapy of cancer. Nat Rev Cancer (2026). https://doi.org/10.1038/s41568-025-00901-z

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