At the Medical University of Vienna, researchers led by Stefan Mereiter have cracked open a puzzle that has long frustrated cancer doctors: why breast tumors—the most common cancer in women—so often ignore immunotherapy drugs designed to wake up the body's own immune defenses. The answer lies in a deceptively simple mechanism: a sugar coating.
The discovery, published in Nature Communications, centers on a process called sialylation, a biochemical modification that tumor cells paint onto their surfaces like biological camouflage. This sugar coating disrupts the conversation between cancer cells and the immune system, allowing tumors to hide in plain sight. When researchers analyzed 136 breast cancer cases, they found that approximately two-thirds of all breast tumors exhibited increased sialylation—and in those cases, significantly fewer T-cells, the immune system's cancer-fighting warriors, were detectable inside the tumor tissue.
The mechanism works in two coordinated ways. First, the sialylation enhances the effect of a growth factor called G-CSF that cancer cells produce and release into the bloodstream. This amplified signal recruits immunosuppressive cells—particularly neutrophils—into the tumor environment, creating a protective barrier that prevents cytotoxic T-cells from penetrating deep enough to attack the cancer effectively. Second, the sugar coating makes tumor cells themselves less recognizable to T-cells that do manage to reach them, allowing the cancer to slip past immune surveillance.
"We were able to show that around two-thirds of all breast tumors exhibit increased sialylation," reports lead author Mereiter. "In these cases, significantly fewer T-cells—immune cells that fight cancer cells—were detectable in the tumor tissue." The finding explains why checkpoint inhibitor immunotherapies, which have revolutionized treatment for many cancers by unleashing the immune system, show only limited effectiveness against breast cancer.
But the research team, including Josef Penninger from the Clinical Institute of Laboratory Medicine at MedUni Vienna, didn't stop at diagnosis. In preclinical models, they tested what happens when sialylation is blocked pharmacologically—and the results were striking. When the sugar coating mechanism was inhibited, T-cells spread throughout the tumor and attacked it far more effectively. More activated cytotoxic T-cells reached the cancer, while immunosuppressive neutrophil cells decreased. Remarkably, even tumor models that had previously resisted immunotherapy began responding to treatment once sialylation was blocked.
The implications are profound. This research suggests that the targeted modulation of tumor sialylation could be a new therapeutic strategy—not to replace immunotherapy, but to make it work. By removing the tumor's sugar disguise, clinicians might be able to restore the immune system's ability to recognize and destroy breast cancer cells that have eluded treatment.
Mereiter and Penninger's work represents the beginning of a new research direction. The findings now form the foundation for additional studies within Mereiter's newly established research group at the Department of Obstetrics and Gynecology at MedUni Vienna, with the explicit aim of developing therapies that could transform breast cancer treatment in the years ahead.