Like spies evading detection through being masters of disguise, many cancer cells are adorned with a copious coat of sugar-derived molecules that throws the proverbial hounds of our immune systems off the scent.
Scientists at Sanford Burnham Prebys Medical Discovery Institute and collaborators across North America published findings August 7, 2026, in Science Advances showing that cancer cells’ cloaking costumes can be a result of changes in the nearby neighborhood of immune cells, connective tissue, blood vessels, proteins and carbohydrates called the tumor microenvironment. The researchers also found a way to thin this sugary shroud, enabling cancer cells to be recognized and eliminated by the immune system.
Lead and corresponding author Kevin Tharp, PhD , knew that cells squeezed by their surroundings change their mitochondrial function in surprising ways. He realized that a key place where cells would experience this kind of physical pressure was in the tumor microenvironment.
“Primary tumors are typically stiffer than their surrounding tissue,” said Tharp, assistant professor in the Cancer Metabolism and Microenvironment Program at the Sanford Burnham Prebys NCI-Designated Cancer Center . “This led me to hypothesize that the biophysical properties of cells influence the altered metabolic programs that everyone observes in tumors.”
One such metabolic alteration considered a hallmark feature of tumors is a drop in the oxidative metabolism of glucose. Prior research has shown that this can be caused by the availability of nearby nutrients and is not necessarily an intrinsic quality of tumor cells.
Tharp and his team compared how cells responded to an abundance of glucose when grown in different environments. Some experienced stiff conditions mimicking what cancer cells face near primary tumors. Others were grown in softer situations similar to normal tissue. Each group was further subdivided to compare two culture media: a conventional laboratory medium and a newer formulation designed to reflect the nutrient composition of the human body. Both media were tested with and without elevated glucose levels to mimic the impact of hyperglycemia.
The scientists found these different conditions altered the proteins produced by cells, the metabolite levels within them and the thickness of their coatings of sugar-derived molecules, known as glycocalyxes. Notably, the depth of this protective barrier was only increased by excess glucose, or hyperglycemia, in cells cultured in the physiological medium.
“We observed that changing the physiological media composition and changing the available metabolites for those tumor cells reveals distinct biology for normal and tumor cell metabolism,” said Tharp.
To see how cell culture characteristics were thickening or thinning cancer cell shells, the scientists looked at how metabolic changes altered the building blocks of the glycocalyx. The glycocalyx is made of carbohydrates conjoined with either proteins or lipids in what are called glycoconjugates. Glucose often provides raw materials for glycoconjugate construction, so the scientists suspected that this assembly process would be affected by changing glucose metabolism or hyperglycemia.
“We found stark separation between the glycoconjugates of cells cultured in conventional medium versus those cultured in a medium that better reflects the nutrient composition of the human body,” said Tharp. Hyperglycemia also affected the makeup of glycoconjugates in cells.
To further explore the link between an overabundance of glucose and glycocalyx thickness, the research team examined which proteins become more abundant in response to hyperglycemia. These experiments pointed to a protein known as heat shock factor 1 (HSF1) for its role in protecting cells from high temperatures and other stresses. HSF1 also has been linked to breast cancer progression and metastasis.
After demonstrating that the presence or absence of HSF1 modified glycoconjugate composition in cells, the scientists tested the connection between hyperglycemia, HSF1, the tumor microenvironment and immune system effectiveness. Their results showed that hyperglycemia boosted cancer cells’ ability to evade the immune system only when HSF1 was present in cells cultured in conditions mimicking the tumor microenvironment. This means that developing drugs to target HSF1 may thin the glycocalyx and prevent cancer cells from avoiding detection by the immune system.
“Our findings indicate that changes in mitochondrial function lead to the synthesis of cell surface sugar-derived molecules that make it difficult for the immune system to recognize and kill cancer cells,” said Tharp. “Now that we know this, this creates an enormous drug discovery opportunity to take away the surface coating that protects them from immune surveillance.
“And we think this will be a really effective strategy to attack metastatic disease and improve immunotherapy responses.”
Tharp also notes that with the rising incidences of metabolic syndrome and type 2 diabetes, hyperglycemia is becoming a bigger risk factor for cancer patients. While there is substantial research linking high blood sugar to an increased risk of developing cancer and worse clinical outcomes following cancer treatment, relatively few studies have examined the biological mechanisms that drive this connection.
“What we found is a plausible mechanism by which hyperglycemia directly contributes to immune evasion,” said Tharp.
“And potentially a way to take away a pro-tumor advantage from hyperglycemia caused by metabolic syndrome and modern diets.”
Additional authors include:
The study was supported by the National Institutes of Health, National Cancer Institute, National Foundation for Cancer Research, Canada Excellence Research Chair in Glycomics and Ovarian Cancer Research Alliance.
The study’s DOI is 10.1126/sciadv.aeb1136 .
Science Advances
Experimental study
Cells
The microenvironment dictates glyco-immune surveillance via HSF1-mediated metabolism
7-Aug-2026
Jason Cantor is an inventor on an issued patent for Human Plasma-Like Medium assigned to the Whitehead Institute. Lara Mahal has done consulting for Vector Laboratories. The Nevan Krogan laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. Nevan Krogan has a financially compensated consulting agreement with Maze Therapeutics, is the president and is on the board of directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, GEn1E Lifesciences and Interline Therapeutics. All other authors declare no competing interests.