Our bodies contain immune cells called macrophages. Normally, these cells attack and suppress bacteria and cancer cells. When macrophages infiltrate tumors, they become tumor-associated macrophages (TAMs) and can switch to an immunosuppressive, anti-inflammatory state.
While "anti-inflammatory" sounds beneficial, in the context of cancer, it means the immune response is suppressed, allowing tumors to grow. It is known that colorectal cancer patients with high levels of anti-inflammatory TAMs tend to have a poorer prognosis.
Researchers at Nagoya University in Japan and their colleagues found that the sialic acid sugar structures on the surface of macrophages change significantly as these cells shift from a tumor-fighting (pro-inflammatory) to a tumor-promoting (anti-inflammatory) state.
The researchers identified an enzyme called ST6GAL1 as a key driver of this change. When they suppressed ST6GAL1 in tumor-promoting macrophages, colorectal cancer cells grew much more slowly in laboratory co-cultures. This suggests that suppressing ST6GAL1 may shift these cells toward a tumor-fighting state, rather than supporting their growth.
These findings were published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The cell surface is covered by the glycocalyx, a layer of proteins and lipids coated with sugar chains. These chains act as mediators of cell communication.
These sugar chains are capped with sialic acid and mainly form two linkage types: α2,3 and α2,6. Altered sialylation is known to help cancer cells evade the immune system, but how these sugars change as macrophages polarize remained unclear.
To investigate this, a team experimentally led by Assistant Professor Priya Dipta of Nagoya University Institute for Glyco-Core Research and Professor Morten Thaysen-Andersen of Macquarie University, Australia, collaborated with Daisuke Kasugai, Hironoshin Onizuka, and colleagues at Nagoya University Graduate School of Medicine.
How glycan chains differ: Tumor-fighting vs. tumor-promoting macrophages
The team isolated monocytes from healthy donors and differentiated them into tumor-fighting and tumor-promoting macrophages to examine glycan linkages. Using mass spectrometry and glycan-specific protein staining, they found that tumor-fighting macrophages had more α2,3-linked sialic acids of N-glycans on the cell-surface, while about 90% of the sialic acids in tumor-promoting macrophages were α2,6.
Using fluorescence microscopy, the researchers observed long, branching protrusions, which they termed sialo-protrusions, coated with α2,6-linked sialic acid. These extended up to 800 micrometers from tumor-promoting macrophages and formed a mesh-like network by connecting nearby cells. Tumor-fighting macrophages displayed far fewer of these structures.
These protrusions showed no evidence of actin, a protein that typically forms cellular extensions. Instead, they carry α2,6-sialylated glycoproteins on their surface, suggesting they may differ from previously reported actin-based cellular protrusions.
Identifying the enzyme responsible for switching glycan chains
The researchers found that only tumor-promoting macrophages express high levels of ST6GAL1. When they suppressed this enzyme using siRNA, the sialo-protrusions broke apart and shortened. The cells also moved less and interacted less with one another.
The macrophages also had less contact with colorectal cancer cells, and the cancer cells grew much more slowly. This suggests that sialo-protrusions help macrophages move, communicate with cancer cells, and support tumor growth through these contacts.
When ST6GAL1 was suppressed, tumor-promoting macrophages began to resemble tumor-fighting ones in shape, cytokine expression, and phagocytic ability. This suggests that targeting a single enzyme can significantly alter macrophage state.
Validation in patient-derived cancer tissue
The team examined tumor tissue from patients with advanced colorectal cancer and found the same pattern of sialic acid linkages as in their laboratory experiments: more α2,6 sialic acid on tumor-promoting TAMs and more α2,3 sialic acid on tumor-fighting TAMs.
Dipta said, "These findings provide a new perspective on how remodeling of the immune cell glycocalyx may influence the tumor microenvironment."
Future studies should test ST6GAL1 inhibition in vivo to evaluate its antitumor potential. The researchers also aim to identify the proteins that form the sialo-protrusions and clarify how these structures mediate communication, in search of new strategies for cancer immunotherapy.
Publication information
Priya Dipta, Naaz Bansal, Arthur Chien, Zeynep Sumer-Bayraktar, Hironoshin Onizuka, Daisuke Kasugai, Dominique Marando, Merrina Anugraham, Seong Beom Ahn, Daniel Kolarich, Boaz Tirosh, Rebeca Kawahara, Arun Everest-Dass, Morten Thaysen-Andersen (2026). ST6GAL1-mediated sialyl linkage switching drives cancer-promoting α2,6-sialo-protrusions radiating from anti-inflammatory TAMs, the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
