Pancreatic cancer is notoriously hard to treat and often resists the most advanced immunotherapies. Northwestern Medicine scientists have uncovered a novel explanation for that resistance: Pancreatic tumors use a sugar-based disguise to hide from the immune system. The scientists also created an antibody therapy that blocks the sugar-mediated "don't-attack" signal.
For the first time, the team identified how this sugar trick works and showed that blocking it with a monoclonal antibody reawakens immune cells to attack cancer cells in preclinical mouse models.
"It took our team about six years to uncover this novel mechanism, develop the right antibodies and test them," said study senior author Mohamed Abdel-Mohsen, associate professor of medicine in the division of infectious diseases at Northwestern University Feinberg School of Medicine.
"Seeing it work was a major breakthrough."
The study was published on Monday, Nov. 3 in the journal Cancer Research (published by the American Association for Cancer Research) to mark the start of Pancreatic Cancer Awareness Month.
Turning the immune system back on
Pancreatic cancer is among the deadliest cancers. It is often diagnosed late, with few treatment options and a five-year survival rate of just 13%. It also tends to resist immunotherapies that work well against other cancers.
Inside pancreatic tumors, the immune system response is unusually suppressed. "We set out to learn why, and whether we could flip that environment, so immune cells attack tumor cells instead of ignoring or even helping them," Abdel-Mohsen said.
The team found that pancreatic tumors hijack a natural safety system used by healthy cells. In normal conditions, healthy cells express a sugar called sialic acid on their surface to signal to the immune system, "don't harm me."
The scientists found that pancreatic tumors exploit that system by loading the same kind of sugar onto a surface protein called integrin α3β1. That sugar coat allows the protein to bind to a sensor on immune cells called Siglec-10, sending a false "stand down" signal.
"In short, the tumor sugar-coats itself - a classic wolf-in-sheep's-clothing move - to escape immune surveillance," Abdel-Mohsen explained.
Creating a new antibody
Once they discovered this novel hiding mechanism, the Northwestern scientists developed monoclonal antibodies that blocked it. When they used those antibodies in the lab and in two animal models, immune cells woke up and began eating cancer cells. Tumors in treated mice grew significantly slower than in untreated controls.
Making those antibodies was no small feat. "When you make an antibody, you test what are called hybridomas, cells that produce antibodies. We screened thousands before finding the one that worked," Abdel-Mohsen said.
The next step, he said, is to combine the antibody with current chemotherapy and immunotherapy treatments. "There's a strong scientific rationale to believe combination therapy will allow us to reach our ultimate goal: a full remission," he said. "We don't want only a 40% tumor reduction or slowing down. We want to remove the cancer altogether."
Moving toward clinical testing
Abdel-Mohsen said his team is now fine-tuning the antibody for human use and moving toward early safety and dosing studies. In parallel, they're testing it in combination with chemotherapy and immunotherapy and developing a companion test to identify which patients' tumors rely on this sugar-based pathway so clinicians can match the right people to the right therapy.
Abdel-Mohsen estimates it might take about five years before such a therapy could be available to patients if progress continues as planned.
Beyond pancreatic cancer, the findings could have broader implications, he said. "We're now asking whether the same sugar-coat trick shows up in other hard-to-treat cancers, such as glioblastoma, and in non-cancer diseases where the immune system is misled."
Abdel-Mohsen's lab focuses on the growing field of glyco-immunology, which studies how sugars regulate the immune system. "We're just scratching the surface of this field," he said. "Here at Northwestern, we're positioned to turn these sugar-based insights into real treatments for cancer, infectious diseases and aging-related conditions."
Abdel-Mohsen is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This paper is titled "Targeting Interactions Between Siglec-10 and α3β1 Integrin Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer." It was supported in part by Northwestern University's Center for Human Immunobiology Pilot Award, 2025-2026 to Abdel-Mohsen. Abdel-Mohsen is also supported by National Institutes of Health grants R01AG092241, R01AI165079, R01AA029859, R01DK123733 R01AI189353 and R01NS117458 and the NIH-funded BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection (1UM1AI126620).
