Scientists at the University of Cambridge have developed a two-part drug system that activates the body’s immune response exclusively inside tumors, offering a potentially safer and more targeted approach to cancer immunotherapy. The research, published this week in Nature Chemistry, centers on the STING pathway short for Stimulator of Interferon Genes a well-known intracellular signaling route that alerts the immune system to the presence of disease.
While STING has been a promising target for cancer treatment, traditional methods of activating it have posed risks, including inflammation and damage to healthy organs. The new approach addresses these challenges by limiting STING activation to tumor tissue. Led by Professor Gonçalo Bernardes from Cambridge’s Yusuf Hamied Department of Chemistry, the research team designed a two-component “prodrug” system. Each of the two components is biologically inert on its own.
When administered to the body, they remain inactive unless they meet under specific conditions present only inside tumors. One of the components contains a molecular structure that is chemically “caged” and unable to react unless it encounters an enzyme called β-glucuronidase, which is found at elevated levels in certain tumors but is scarce in healthy tissues. Once this enzyme removes the protective cage, the component becomes reactive and binds with the second molecule, forming the active drug.
Scientists develop tumor-specific STING drug at Cambridge
This newly formed compound then triggers the STING pathway, prompting the immune system to attack cancer cells. Laboratory tests confirmed that the individual components had negligible biological activity in isolation. However, in tumor-like environments containing β-glucuronidase, the two compounds combined to form an active STING agonist. In zebrafish and mouse models engineered to mimic human tumors, the drug was activated almost exclusively within tumor sites, with minimal exposure to vital organs including the liver, kidneys, and heart.
In a mouse model of colorectal cancer modified to overproduce β-glucuronidase, the two-component system led to measurable tumor suppression and improved survival rates, while avoiding the systemic toxicity often seen with conventional STING agonists. Animals receiving the new therapy exhibited stable body weight and showed no signs of tissue damage in non-cancerous organs. The researchers achieved this tumor specificity through a design that allows the two molecular components to find and react with each other rapidly once the first part is uncaged.
Study confirms minimal systemic exposure with new approach
The strategy avoids the need for external catalysts or complex activation systems, relying instead on naturally occurring tumor enzymes and basic chemical affinity. The work represents a technical advance in the application of immunotherapy, showing that targeted drug assembly inside diseased tissue is possible through chemical design. It also addresses a longstanding limitation of STING agonist treatments, which have struggled to differentiate between healthy and malignant tissue, often leading to off-target effects and limited clinical success.
According to the study, the two-part drug system maintained its precision and potency at very low concentrations, indicating potential for reduced dosing in future therapeutic use. The chemical stability of the individual components also makes them viable for further testing in preclinical and clinical settings. The full findings were peer-reviewed and published in Nature Chemistry on September 16. The study was supported by researchers across multiple disciplines at the University of Cambridge and affiliated institutions. – By EuroWire News Desk.