Immunotherapy, a form of cancer treatment that often requires expensive hospital-based injections, may one day be available in the form of a simple pill.

A team of Chinese scientists led by Fudan University in Shanghai has developed a new method for targeted protein degradation that could revolutionize how we treat cancer, metabolic disorders and neurological diseases. The research was published on Thursday on the website of the journal Cell.

Scientists often compare a cell to a factory where proteins are the primary products. Within this factory, a structure called the endoplasmic reticulum, or ER, acts as a quality control workshop.

Its job is to find misfolded proteins and mark them for disposal in the proteasome, which functions as the cell's version of a trash compactor.

This natural cleaning process is known as the ER-associated degradation, or ERAD, pathway. Until now, scientists believed ERAD mainly handled misfolded proteins. However, the Fudan team discovered they could hijack the system to destroy specific proteins that cause disease.

While current drugs are effective in attacking proteins inside a cell's fluid, they often struggle to destroy transmembrane proteins. These proteins are embedded in the cell's outer skin or membrane and often act as the "locks" that cancer uses to hide from the immune system.

The researchers created a bridge using a small molecule compound. This bridge links a specific enzyme in the ER's quality control workshop directly to a harmful transmembrane protein, which is typically produced and folded on the ER.

By tethering the harmful protein to the ER enzyme and subsequently triggering its entry into the ERAD pathway, the cell treats the disease-causing protein as trash and destroys it autonomously. The researchers name this novel strategy ERADEC, for ERAD engaging chimeras.

The team tested this strategy on PD-L1, a protein that cancer cells use as a shield to avoid being attacked by the immune system.

In human immune cells reconstituted mouse models, the new strategy was more effective at shrinking tumors than the PD-L1 antibody injections currently used in hospitals.

"The discovery may open up a paradigm shift in drug development targeting transmembrane proteins. Unlike current antibody treatments — which are made of large biological molecules that must be injected — ERADEC may enable the design of new small molecule degraders that are cheaper to produce and easier to deliver," said Lu Boxun, lead researcher and professor at Fudan University's School of Life Sciences.

While the specific compound used in the study is not yet ready to be swallowed as a pill, the researchers said they have already developed ERADEC molecules that show oral bioavailability. This means the body can absorb the drug through the digestive system rather than requiring an intravenous line.

This technology also shows platform potential, said Lu. By simply changing one part of the molecule, scientists can target different illnesses ranging from Alzheimer's to chronic pain.

If successful, patients of the future could manage their immunotherapy at home, avoiding frequent hospital visits and reducing the cost of care.

zhouwenting@chinadaily.com.cn