# Core Fucosylation Represses SMURF1‐Dependent Degradation of CD47 to Promote Tumor Immune Evasion

## TL;DR

Core fucosylation of CD47 helps tumors avoid immune detection by reducing its degradation, and blocking this process enhances anti-tumor immune responses.

## Contribution

The study identifies a novel mechanism where FUT8-mediated core fucosylation of CD47 prevents its degradation, promoting tumor immune evasion.

## Key findings

- Core fucosylation of CD47 at N111 reduces ubiquitination and degradation via SMURF1.
- Blocking CD47 glycosylation increases macrophage phagocytosis and DC/NK cell infiltration.
- FUT8 levels correlate with CD47 expression and immune cell infiltration in human HCC.

## Abstract

Glycosylation, the covalent attachment of glycans to proteins, lipids, and RNAs, is fundamental in regulating diverse biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment and closely associated with tumor immune escape. However, the molecular mechanisms by which glycosylation regulates tumor immune escape are poorly understood. We show that Cluster of Differentiation 47 (CD47), an innate immune checkpoint protein, is highly modified with core fucosylated N‐linked glycans. Core fucosylation of CD47 mediated by fucosyltransferase 8 (FUT8) at asparagine 111 (N111) reduces CD47 ubiquitination and degradation. Blockade of N111 glycosylation represses CD47 expression and promotes macrophage phagocytosis of tumor cells. Furthermore, elimination of N111 glycosylation promotes the infiltration of CD103+ dendritic cells (DCs), leading to the increased recruitment of natural killer (NK) cells and inhibition of tumor growth in a murine hepatocellular carcinoma (HCC) model. Combined treatment with core fucosylation inhibitors and an anti‐CD47 antibody synergistically promotes therapeutic efficacy in the HCC model. Finally, FUT8 levels in human HCC specimens are positively correlated with CD47 expressions and negatively correlated with the infiltration of CD103+ DC and NK cells. Collectively, this study reveals a mechanism underlying CD47 upregulation in tumor cells and highlights the potential of targeting the FUT8‐SMURF1‐CD47 axis as a therapeutic strategy to improve anti‐tumor immune responses.

FUT8‐mediated core fucosylation of CD47 at N111 blocks SMURF1 binding and reduces CD47 ubiquitination and degradation. Blocking N111 glycosylation reduces CD47 expression and promotes macrophage phagocytosis of tumor cells. Furthermore, ablating CD47 core fucosylation boosts CD103+ dendritic cells (DCs) infiltration, increases natural killer (NK) cell recruitment, and suppresses tumor growth.