Light-Activated Switch and Master Regulator Studies Expose Vulnerabilities in Hard-to-Treat Lung Cancers

Researchers are exposing new vulnerabilities in hard-to-treat lung cancers, with two separate studies offering potential paths to more effective therapies. A team at ETH Zurich has developed a light-controlled molecular switch that wakes lung cancer cells from a protective dormant state, while scientists at Cold Spring Harbor Laboratory have uncovered molecular master regulators that allow certain carcinomas to resist treatment.

Tumor cells can lapse into a sleep-like state and thereby evade the destructive effect of cancer drugs. In some types of the disease, such as certain forms of lung cancer, this state is triggered by stress hormones in the body. Inside the cancer cells, glucocorticoid receptors recognize the hormones, and the cells respond by lapsing into a state in which they undergo barely any division, rendering many treatments ineffective. Scientists are attempting to switch off these receptors with a view to waking the cancer cells up from sleep, making them vulnerable to attack.

Every cell in the body has glucocorticoid receptors, which perform important functions, including reducing inflammation and supporting the immune system. Eliminating all these receptors throughout the body would have disastrous side effects, so a highly specific method is needed. The ETH Zurich researchers built a switch made up of three parts: a sub-unit that binds to the receptor, a flexible connecting piece, and another sub-unit that binds to the enzyme responsible for attaching a 'rubbish' label. In normal lighting conditions, the connecting piece is stretched so that the enzyme is at the correct distance from the receptor to mark it, and the cell breaks up and disposes of the receptor. When exposed to light of a given wavelength, the connecting piece becomes kinked, preventing the labels from being attached.

The system is injected into the tumor, and light is used to specifically turn off all switches that migrate from the tumor into the healthy tissue. Activity can therefore be strictly limited to the tumor core, preserving the surrounding tissue and causing significantly fewer side effects. According to the researchers, the effect is reversible and can be controlled precisely. In lab cultures of lung cancer cells, the active substance led to a rapid breakdown of the tumor cells' glucocorticoid receptors, and an analysis of genetic activity showed that the cells were woken from their dormant state. The researchers noted the next step is to verify the effect in living organisms. They also aim to develop switches that respond to longer wavelengths, such as near-infrared, which penetrate deeper into tissue.

Separately, Cold Spring Harbor Laboratory (CSHL) scientists have uncovered important weaknesses in hard-to-treat carcinomas. Certain cancers are extremely difficult to treat because they can shift their identity, taking on characteristics of cells from entirely different organs, including skin. 'The tumors are notoriously plastic in their cellular identity,' said a CSHL professor. This flexibility allows tumors to adapt and survive treatment.

In a study published in Nature Communications, the researchers identified a protein that controls whether pancreatic cancer cells keep their traditional identity or begin to resemble and behave like skin cells. In separate work reported in Cell Reports on 18 November 2025, the team determined the crystal structure of another group of proteins central to tuft cell lung cancer. Tuft cell lung cancer was first identified in 2018, and the researchers have been searching for epigenetic drivers of tumor growth. The findings could eventually form the basis of an epigenetic therapy aimed at stopping tumor growth.

The long-term objective, according to the researchers, is to identify the master regulators of cellular identity and develop therapies that target them, similar to how hormone treatments transformed care for breast and prostate cancers. In mouse models of pancreatic and lung cancer, the researchers observed no signs of toxicity or injury to major organs. 'We're setting a higher bar for specificity when it comes to new cancer targets and treatments,' the CSHL professor said.