Scientists have reported a breakthrough in treating solid tumor cancers using a Velcro-like tool that targets glycans, surface sugars especially abundant in cancer cells. This potentially off-the-shelf therapy does not need adjustment to individual cancer types or patients.
No sugarcoating this
Antibody-based cancer immunotherapies, such as chimeric antigen receptor T (CAR-T) cells were once hailed as gamechangers in oncology. While their potential is indeed massive, several major hurdles remain. For instance, such tools need very high affinity to kill tumors, but that high affinity means they risk hitting the same target on normal tissues, where it can be present in low numbers (“on-target, off-cancer” toxicity) [2]. Moreover, targets tend to be specific to a cancer type or even a particular tumor, requiring expensive tailor-made approaches.
One of the most widespread adaptations that help cancer cells grow and propagate while evading the immune system is a remodeled glycocalyx, which is a cellular coating of glycans linked to proteins and fats (glycoproteins, glycolipids, proteoglycans) [3]. Tumors often thicken and re-pattern these sugars into tumor-associated carbohydrate antigens (TACAs), which can hide danger signals from immune cells, boost growth, and make it physically harder for immune cells to latch on.
However, this glycocalyx remodeling also differentiates cancer cells from the rest and provides an opportunity to target them. If we find a way to target TACAs safely, we can get a single approach that works across many tumors while sparing healthy cells. This idea is at the heart of a new study from the University of California Irvine, published in the journal Cell.
The two-armed bandit
The researchers used sugar-binding proteins called lectins in a way that causes many weak grips to add up (avidity), which the authors liken to Velcro, rather than the single high-affinity “key-lock” connection characteristic of antibodies. They created a bispecific protein that fuses a lectin carbohydrate-recognition domain (CRD) to a single-chain antibody.
Bispecificity means that one arm of the protein, containing four lectins, like four Velcro hooks, latches on to the glycans on the cancer cell’s surface, while the other arm attaches itself to a T cell, bringing it into proximity with the cancer cell. The researchers hypothesized that this construct, glycan-dependent T-cell recruiter (GlyTR, pronounced “glitter”), would recruit T cells to high-TACA-density cancer cells but not to normal cells, where glycan density is much lower.
“It’s the holy grail – one treatment to kill virtually all cancers,” said Michael Demetriou, MD, Ph.D., a professor of neurology, microbiology and molecular genetics at the UC Irvine School of Medicine and the paper’s corresponding author. “GlyTR’s velcro-like sugar-binding technology addresses the two major issues limiting current cancer immunotherapies: distinguishing cancer from normal tissue and cancer’s ability to suppress the immune system.”
The researchers confirmed that the GlyTR’s lectin arm binds to cancer cells but not to the T cells that GlyTR engages. They also tested GlyTRs on several types of healthy tissues and red blood cells (RBCs), confirming there was no strong interaction with non-cancer cells or concerning accumulation in normal organs in vivo.
Effective against multiple cancers
For cancer, however, the effect was devastating. In vitro, both GlyTR versions created by the researchers, GlyTR1 and GlyTR2, bound a wide variety of solid and liquid tumors, including breast, ovarian, prostate, pancreatic, colon, lung, AML, myeloma, and T-cell leukemia, much more than normal lymphocytes and drove T-cell-dependent killing even at very low concentrations. Notably, conventional immunotherapies mostly work for blood cancers, while solid tumors proved to be much harder to crack.
For their in vivo experiments, the team used immunodeficient mice given human T cells (humanized NSG mice) and implanted rejection-proof human tumors. When they injected fluorescent GlyTRs into the bloodstream, the proteins homed to lungs that harbored metastatic triple-negative breast cancer (TNBC) but not to lungs without tumors, providing evidence of tumor-seeking behavior in vivo.
In intraperitoneal models of TNBC, pancreatic, and ovarian cancers, GlyTRs produced dramatic response compared to just human CD8+ T cells, completely blocking tumor growth. The ovarian cancer model was independently replicated at the National Cancer Institute in a good sign for future clinical trials.
Clinical grade GlyTR1 protein manufacturing is already being developed at the NCI Experimental Therapeutics program labs in Maryland. Due to these phenomenal results, the team plans to bring the project to the clinic as early as possible, with human trials in about two years from now, according to the press release.
“This is the revolutionary approach to cancer treatment our patients have been waiting for,” said Farshid Dayyani, MD, Ph.D., medical director of the Stern Center for Clinical Trials and Research. “We are committing all available resources to bring this exciting new trial to UCI Health as fast as possible.”
Literature
[1] Zhou, R. W., Purohit, P. K., Kim, J. H., Newton, B. L., Edwards, R. A., & Demetriou, M. (2025). Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens. Cell, 188, 1–17.
[2] Lamers, C. H., Sleijfer, S., Van Steenbergen, S., Van Elzakker, P., Van Krimpen, B., Groot, C., … & Gratama, J. W. (2013). Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Molecular therapy, 21(4), 904-912.
[3] Buffone Jr, A., & Weaver, V. M. (2019). Don’t sugarcoat it: How glycocalyx composition influences cancer progression. Journal of Cell Biology, 219(1), e201910070.
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