Researchers at ETH Zurich have developed a molecular switch that is controlled by light. It awakens lung cancer cells from their protective dormant state, making them more amenable to treatment.
Tumor cells enter a sleep-like state, which allows them to avoid the destructive effects of cancer drugs. In some types of diseases, such as certain lung cancers, this condition is caused by stress hormones in the body. Within cancer cells, glucocorticoid receptors recognize the hormone, and the cells respond by becoming less likely to divide. This makes many treatments ineffective. Scientists are trying to switch off these receptors with the aim of waking cancer cells from sleep and making them more vulnerable to attack.
Light limits its effect on tumors
The problem is that every cell in our body has glucocorticoid receptors, which serve important functions such as reducing inflammation and the immune system. Removing all of these receptors in the body has disastrous side effects, so highly specific methods are needed to destroy only the glucocorticoid receptors on tumor cells.
Researchers at ETH Zurich found a solution by developing a system that induces the destruction of these receptors. Light can be used to selectively neutralize the system’s effects on surrounding healthy tissue and limit the effects to the tumor. “This system is based on existing medical technology and therefore offers a realistic prospect for local therapy,” says Robin Schoplin, co-lead author of the publication and a doctoral student in the research group led by Professor of Epigenetics and Neuroendocrinology Katharina Gapp.
Tagging ensures rapid disposal of receptors
The researchers took advantage of the body’s naturally occurring recycling system for this approach. The system detects defective proteins and tags them for disposal by labeling them with small molecules, or “garbage” so to speak. Proteins labeled in this way are degraded. The researchers have now modified this process to specifically deal with glucocorticoid receptors on tumor cells.
To do so, they built a switch that consists of three parts. A subunit that binds to the receptor, a flexible connector, and another subunit that binds to the enzyme responsible for labeling the trash. The secret lies in the chemical design of the connecting part. Under normal lighting conditions, the connection is stretched so that the enzyme is located at the appropriate distance from the receptor to mark it. Therefore, the cell receives a signal to destroy and dispose of the receptor. When exposed to certain wavelengths of light, the connections twist. As a result, the enzyme and receptor no longer have the correct relative positions to label the trash.
Lung cancer cells awaken from sleep in the lab
This scientific development was made possible by collaboration between different research groups at ETH Zurich. For these experiments, organic synthesis professor Eric Carrera and his team created multiple connecting pieces. When incorporated into a switch, two of these components exhibited exactly the desired characteristics during testing. This means that light could be used to flip the switch between forms that induce receptor degradation and those that do not.
We aim to apply this switch to highly accurate local cancer treatment. For this purpose, we inject it into the tumor and then use light to specifically turn off all the switches that migrate from the tumor to the healthy tissue.
Therefore, activity can be strictly restricted to the tumor center, protecting surrounding tissues and significantly reducing side effects. This effect is reversible and can be precisely controlled. ”
Robin Scheuplein, co-lead author of this publication
Researchers have already succeeded in demonstrating the expected biological effect of the active substance in laboratory cultures of lung cancer cells, causing rapid destruction of glucocorticoid receptors on tumor cells. Analysis of gene activity also showed that cells wake up from dormancy as a result. “Of course, we’ll need to test this in vivo in the future,” says Schoplin.
Application to breast and prostate cancer
Additionally, researchers need to optimize the system for cancer treatment applications. Because light only penetrates a few millimeters into the tissue, the light source must be placed close to the tumor border to establish a protective optical barrier. For example, in the case of lung cancer, this can be easily achieved using an endoscope. For deeper-lying tumors, the research team hopes to develop a switch that responds to longer wavelengths, such as near-infrared light, that penetrate deeper into the tissue more gently.
“We developed a modular system that can also be used to switch off other receptors,” Scheuplein explains. For example, receptors of interest for clinical applications include estrogen receptors in hormone-dependent breast cancer and androgen receptors in advanced prostate cancer. This system is already ready for use in research to elucidate complex signaling pathways in cancer biology.
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Reference magazines:
Friday, K.M. Others. (2026). Photo-controlled destruction of the dormant state of cancer cells via photoswitchable stress hormone receptor degraders. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2528760123. https://www.pnas.org/doi/10.1073/pnas.2528760123
