POSTECH team pioneers new cancer therapy strategy: targeting GLUT3 in regulatory T cells to supercharge anti-tumor immunity

Scientists at Pohang University of Science and Technology (POSTECH) and ShanghaiTech University have achieved a breakthrough in cancer immunotherapy research. Led by Professors Sin-Hyeog Im and Dipayan Rudra, the research team, with Dr. Amit Sharma as the first author, has identified GLUT3, a glucose transporter, as essential to the suppressive function of regulatory T cells (Tregs) in the tumor microenvironment (TME). This discovery provides new insights into immune cell metabolism within tumors and highlights GLUT3 and glucose-mediated protein modifications as promising targets for cancer immunotherapy. Their findings were published in the latest issue of Cellular & Molecular Immunology.

T cells are central to the body’s defense against cancer, with one subset, regulatory T cells (Tregs), playing a unique and often contradictory role in immune response. Unlike conventional T cells that attack tumors, Tregs prevent excessive inflammation and maintain immune tolerance. While this is essential for immune balance, Tregs within tumors, known as tumor-infiltrating Tregs (TIL-Tregs), allow cancer to evade immune attacks by suppressing the activity of effector T cells—the immune cells that actively target and kill tumor cells. Although targeting Tregs to restore anti-tumor immunity is an emerging area in cancer therapy, systemically inhibiting Tregs can cause severe autoimmune reactions. This challenge has focused researchers on understanding Tregs’ tumor-specific mechanisms to selectively target Tregs within tumors without impacting the immune system as a whole.

Professor Im explains that TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the TME, where effector T cells often falter. This resilience inspired the team to investigate glucose uptake and utilization in TIL-Tregs, leading them to identify the critical role of GLUT3. While GLUT1 is the primary glucose transporter in conventional T cells, GLUT3 plays a central role in glucose metabolism in TIL-Tregs. Typically associated with neurons, GLUT3 enables TIL-Tregs to efficiently absorb glucose from the TME, supporting their suppressive activity. The team found that high expression of GLUT3 (encoded by the gene SLC2A3) and Treg infiltration correlate with poorer outcomes in various cancers, while GLUT1 (SLC2A1) does not have the same impact. In a genetically engineered mouse model, the researchers demonstrated that selectively removing GLUT3 in Tregs significantly reduced tumor growth without affecting the Tregs' normal functions, opening a new therapeutic pathway.

The team further explored how glucose uptake sustains TIL-Tregs’ suppressive power. Through RNA sequencing, metabolomics, and isotope-tracing studies, they discovered that GLUT3-driven glucose absorption activates a metabolic pathway leading to protein modification with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a sugar molecule. This modification process, called O-GlcNAcylation, regulates various proteins, including the transcription factor c-Rel, which is essential for TIL-Tregs’ tumor-specific properties. By facilitating O-GlcNAcylation, GLUT3 provides TIL-Tregs with a metabolic advantage that enhances immune suppression within tumors.

Interestingly, the researchers found that increasing protein O-GlcNAcylation in GLUT3 knock-out Tregs—using an enzyme inhibitor called Thiamet-G—led to greater tumor growth, further confirming the link between GLUT3-driven O-GlcNAcylation and TIL-Treg function. Analysis of TIL-Tregs from human colon cancer patients validated this relationship, showing elevated levels of c-Rel O-GlcNAcylation in the tumor environment.

This research highlights that TIL-Tregs have unique metabolic adaptations, enabling them to thrive in the TME and effectively suppress immune responses. By pinpointing GLUT3’s critical role in shaping TIL-Treg functionality, the study lays the groundwork for developing targeted therapies that could boost anti-tumor immune responses without compromising overall Treg function, thus minimizing the risk of autoimmune side effects. Dr. Amit Sharma, the study’s lead author and a postdoctoral researcher in Professor Im’s lab, emphasized the significance of GLUT3 in defining TIL-Tregs’ functionality, noting, “It will be fascinating to explore how different modes of glucose transport influence the metabolic fate of glucose within cells,” underscoring the potential of GLUT3-targeted therapies to strengthen anti-tumor immunity.

In conclusion, the discovery points to a promising direction for future cancer therapies by identifying metabolic vulnerabilities in TIL-Tregs, paving the way for innovative strategies in cancer immunotherapy that focus on rebalancing immune responses while minimizing adverse effects. Targeting GLUT3 or the O-GlcNAcylation pathway could precisely manipulate Treg activity within tumors, leading to better outcomes in cancer patients.