Cancer Immunotherapy Pill on the Horizon Thanks to Fudan University Breakthrough
Immunotherapy, a powerful cancer treatment often requiring frequent hospital-based injections, may one day be accessible as a simple pill. A team of scientists led by Fudan University in Shanghai has developed a novel method for targeted protein degradation that could revolutionize the treatment of cancer, metabolic disorders, and neurological diseases. The research was published in the journal Cell.1
Understanding the Cellular “Trash Compactor”
Cells function much like factories, with proteins as their primary products. Within this cellular factory, the endoplasmic reticulum (ER) acts as a quality control workshop, identifying misfolded proteins and marking them for disposal by the proteasome – essentially the cell’s “trash compactor.”
This natural cleaning process is known as ER-associated degradation (ERAD). Traditionally, ERAD was believed to primarily handle misfolded proteins. However, the Fudan University team discovered a way to hijack this system to selectively destroy specific proteins that contribute to disease.
Targeting Transmembrane Proteins: A Key Challenge
Current drugs effectively target proteins within a cell’s fluid, but often struggle to destroy transmembrane proteins. These proteins are embedded in the cell’s outer membrane and frequently act as shields that cancer cells utilize to evade the immune system.1
ERADEC: A Novel Strategy for Protein Degradation
The researchers created a “bridge” using a small molecule compound. This bridge connects a specific enzyme within 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 triggering its entry into the ERAD pathway, the cell recognizes the disease-causing protein as waste and destroys it. This innovative strategy has been named ERADEC, short for ERAD engaging chimeras.1
Promising Results in Tumor Models
The team tested ERADEC on PD-L1, a protein cancer cells use to avoid immune system attacks. In human immune cells reconstituted mouse models, the new strategy demonstrated greater effectiveness in shrinking tumors compared to current PD-L1 antibody injections administered in hospitals.1
Potential for Affordable and Accessible Immunotherapy
“The discovery may open up a paradigm shift in drug development targeting transmembrane proteins,” said Lu Boxun, lead researcher and professor at Fudan University’s School of Life Sciences. “Unlike current antibody treatments – which are large biological molecules requiring injection – ERADEC may enable the design of new small molecule degraders that are cheaper to produce and easier to deliver.”1
While the initial compound isn’t yet suitable for oral administration, the researchers have already developed ERADEC molecules exhibiting oral bioavailability, meaning the body can absorb the drug through the digestive system, eliminating the need for intravenous lines.1
Platform Potential for Diverse Diseases
This technology also demonstrates significant platform potential. According to Lu, simply modifying one part of the molecule allows scientists to target different illnesses, ranging from Alzheimer’s disease to chronic pain.1
Successful development of ERADEC could allow patients to manage their immunotherapy at home, reducing the frequency of hospital visits and lowering healthcare costs.1
Recent Advances in Immunotherapy Research
Recent research highlights the growing importance of understanding the immune response to cancer. A study published in November 2023 details how scCURE (single-cell RNA sequencing data-based Changed and Unchanged cell Recognition during immunotherapy) can identify cell types responding to immunotherapy.1 Nobel Laureate Bertozzi has noted that immunotherapy has already cured some cancer patients.2 Research into CAR-T cell immunotherapy, conducted at Fudan University, continues to advance cancer treatment options.3 Weiguo Hu, a professor at Fudan University Cancer Institute, is investigating the role of the complement system in cancer therapy resistance, and immunotherapy.4
Worth a look