Two-part prodrug system activates immune attack only in tumor’s unique environment by University of Cambridge

Scientists have developed a smarter way to activate the immune system against cancer, potentially making treatments safer and more precise.

The research focuses on a powerful pathway inside our cells known as STING. When triggered, STING acts like an internal alarm system, sending out signals that summon the body’s immune system to attack. Their results are reported in the journal Nature Chemistry.

Drugs that activate this pathway have shown promise in cancer therapy, but until now, they have faced a major problem: if switched on in healthy tissues, they can cause harmful and sometimes dangerous side effects.

To solve this problem, researchers from the University of Cambridge designed a two-part “prodrug” system, made of two harmless components that only activate when they meet in a tumor.

One component of the drug was “caged” so that it remains inactive until it encounters a tumor-specific enzyme called β-glucuronidase, which is rarely found in healthy tissue. When the caged component meets this enzyme inside a tumor, it is unlocked and reacts with the second component.

Together, the two pieces form a powerful STING activator, switching on the immune system only where the cancer is located. The molecules are designed to recognize and stick to each other efficiently, so the reaction happens quickly and selectively inside tumors.

“This is like sending two safe packages into the body that only unlock and combine when they meet the tumor’s unique chemistry,” said Professor Gonçalo Bernardes from Cambridge’s Yusuf Hamied Department of Chemistry, who led the research.

“The result is a strong immune-activating drug that appears only where it is needed.”

Laboratory experiments showed that the two drug components have almost no activity on their own. But when they met in tumor conditions, the active compound formed and successfully triggered STING at very low concentrations. In zebrafish and mouse models engineered to produce β-glucuronidase, the drug became active almost exclusively in the tumors, sparing vital organs such as the liver, kidney, and heart.

This level of precision represents a major advance for STING-based therapies, which have previously struggled to distinguish between healthy and cancerous tissues. By using a simple chemical design, the Cambridge team achieved targeted activation of the immune system without relying on complex or artificial reactions.

Beyond cancer, the researchers believe this method could inspire a new class of precision medicines. The concept of safe, separate components that only form active drugs at the disease site could be applied to other illnesses where strong drugs must be delivered safely.

“This discovery is exciting not only for cancer treatment, but also as a new way of thinking about how we make medicines safer and more precise,” said first author Nai-Shu Hsu, also from the Department of Chemistry.

Inactivation of key pathway boosts the body’s immune response against tumors