Professor Yujahyeong’s team develops protein degradation technology to enhance targeting of cancer cells
Reduction of PD-L1 protein levels and tumor size, published in Advanced Science.
A technology has been developed that breaks down proteins used by cancer cells to evade immune attacks, thus killing the cancer cells. The research team, led by Professor Yujahyeong of the Chemistry Department at UNIST, has developed a complex assembly technology that degrades proteins used by cancer for immune evasion. This technology works by trapping immune-evasion proteins within a complex and sending them to lysosomes where protein degradation occurs. This is expected to enhance the cancer treatment effect by creating an environment where the immune system can recognize and eliminate cancer cells.
Cancer cells produce more of the protein PD-L1 than normal cells and display it on the cell surface. This protein communicates a “do not attack” signal to immune cells, allowing cancer cells to rapidly proliferate while evading the body’s immune surveillance. The research team developed a technology based on acetazolamide to selectively degrade PD-L1 in cancer cells. Acetazolamide attaches to the CAIX enzyme present on the surface of cancer cells to form a protein nano-complex, which pulls immune-avoidance proteins like PD-L1 into the cell. Inside the cell, the nano-complex is recognized as an abnormal protein and is broken down in the cell’s cleaning factory, the lysosome. Since CAIX enzyme is rarely found in normal cells, this reaction is specific to cancer cells.
Cancer cells lacking PD-L1 protein become targets for immune cell attacks. Animal experiments using mice showed that groups injected with this complex experienced a reduction in tumor size to less than half and a noticeable decrease in PD-L1 protein levels.
First author Dohyun Kim stated, “We plan to further elucidate the pathway through which the immune system directly attacks cancer.” Although existing protein degradation technologies like PROTAC and LYTAC use chimeric molecules, they face challenges of being large, having difficulty entering cells, and being complex to design and synthesize. This research proposes a new method to overcome the limitations of existing technologies by allowing molecules to assemble on their own within the body.
Professor Yujahyeong mentioned that this is “a new form of targeted protein degradation technology that surpasses the limitations of existing polymer-based chimeric technologies” and that it could potentially be applied in combination with immunotherapy or for treating various refractory solid tumors.
The research results were published in the international journal Advanced Science on April 3rd, supported by the Ministry of Science and ICT and the National Research Foundation of Korea.