Arbor Assays

Hijacking Immunity: Cancer Cells Use Fumarate to Evade STING Activation

In the ongoing battle between cancer and the immune system, the cGAS–STING pathway is one of the body’s earliest defenders. When cytoplasmic DNA is detected, often a sign of infection, tissue damage, or tumor stress, cGAS (cyclic GMP-AMP synthase) catalyzes the production of cyclic GMP-AMP (cGAMP). This second messenger activates STING (stimulator of interferon genes). STING is a protein anchored in the endoplasmic reticulum that triggers type I interferon and pro-inflammatory signaling. Once activated, STING initiates a cascade of immune and inflammatory responses, recruiting T cells and natural killer cells to eliminate abnormal cells. 

But what if cancer could short-circuit this alarm system? A recent study published in Nature Cell Biology reveals how triple-negative breast cancer (TNBC) cells reprogram their metabolism to suppress STING activation, and how Arbor Assays’ 2′,3′-Cyclic GAMP ELISA Kit helped uncover this immune evasion strategy. 

cGAMP Levels Stay High, but STING Stays Silent 

To investigate how breast cancer evades immune detection, Duan et al. compared STING signaling in normal versus TNBC cells under hypoxic stress (low oxygen conditions, common in tumors). While normal mammary epithelial cells activated STING as expected, TNBC cells did not, despite producing similar amounts of intracellular cGAMP. 

This malignant silence suggested that the blockage was not at the level of cGAMP synthesis but farther downstream. Using Arbor Assays’ cGAMP ELISA Kit (K067-H), the researchers accurately measured cGAMP levels and confirmed that cGAS activity was intact. The problem, they discovered, was how STING was being suppressed after cGAMP was produced. 

Fumarate Disrupts STING activation 

Adenylosuccinate lyase (ADSL), an enzyme involved in purine metabolism, was found to be overexpressed in TNBC cells. Under hypoxic conditions, it becomes phosphorylated and relocates to the endoplasmic reticulum, where it interacts with STING. 

Once there, ADSL produces fumarate, a metabolite that binds to the same site on STING as cGAMP. This effectively blocks its activation even with cGAMP present. Arbor Assays’ ELISA kit enabled the research team to demonstrate that overall cGAMP levels were unaffected, indicating that the inhibition was due to fumarate, rather than a failure to produce cGAMP. 

The metabolic suppression of STING signaling has significant clinical implications. It correlates with poorer outcomes in breast cancer patients and represents a novel mechanism of tumor immune evasion. 

New Strategies for Immuno-Oncology 

These findings highlight a fascinating connection between cancer metabolism, innate immune sensing, and inflammation. By interfering with STING at the ligand-binding site, TNBC cells not only evade immune detection but also disrupt key inflammatory signaling pathways that would otherwise amplify antitumor responses. 

The research also opens the door to new therapeutic strategies. Inhibiting ADSL’s translocation or its interaction with STING could restore immune signaling and potentially improve the effectiveness of checkpoint inhibitor therapies. 

Enabling Deeper Insight into Immune Resistance 

As cancer immunotherapy continues to evolve, so does the need for precise tools to monitor and dissect immune pathways. The 2′,3′-cyclic GAMP ELISA Kit was crucial in uncovering how cancer cells metabolically suppress STING activity. By helping researchers pinpoint where and how this suppression occurs, the kit supports a deeper understanding of immune resistance and strategies to overcome it. 

Whether you’re investigating inflammatory signaling, immune activation, or cancer metabolism, Arbor Assays’ kits provide the precision and reliability researchers need to uncover hidden mechanisms and identify new therapeutic opportunities. 

What to learn more? Discover our comprehensive range of assay kits to support your next breakthrough. 

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