MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint

Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2215376120. doi: 10.1073/pnas.2215376120. Epub 2023 Mar 10.


The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.

Keywords: MYC; Siglec; glycosylation; oncogene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Humans
  • Ligands
  • Macrophages / metabolism
  • Mice
  • Neoplasms* / metabolism
  • Proto-Oncogene Proteins c-myc* / metabolism
  • Sialic Acid Binding Immunoglobulin-like Lectins* / metabolism


  • Antigens, CD
  • Ligands
  • Sialic Acid Binding Immunoglobulin-like Lectins
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc