Protein Tool Harnesses Phagocytosis to Remove Harmful Cells

Every day, billions of damaged or unnecessary cells die and are swept away by the immune system’s cleanup crew—phagocytes. But when that clearance falters, dangerous cells can linger, fueling cancer and autoimmune disorders, among others.

Now, scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) have developed a protein-based therapeutic tool designed to redirect this cleanup process. The new tool, called Crunch—short for Connector for Removal of Unwanted Cell Habitat—reprograms the body’s natural waste disposal system to selectively eliminate harmful living cells. Their study, “Phagocytic clearance of targeted cells with a synthetic ligand,” appears in Nature Biomedical Engineering.

The immune system relies on phagocytes to recognize and engulf dying cells tagged with an “eat-me” signal. This process, called phagocytosis or, more specifically, efferocytosis, is crucial for keeping tissues healthy. But until now, it has never been used to deliberately target living, disease-causing cells.

“What we’ve done is take that natural cleaning system and reprogram it to target living cells that shouldn’t be there,” explained first author Yuki Yamato of the Graduate School of Biostudies at Kyoto University. “We built Crunch by modifying a protein called Protein S, which normally helps phagocytes recognize dead cells. But instead of binding to dead cells, we gave Crunch the ability to recognize specific living cells we want to remove, like cancer cells or overactive immune cells in autoimmune diseases.”

To achieve this, the researchers swapped out the domain of Protein S that normally detects dying cells and replaced it with modular “sensors” that bind surface proteins unique to unwanted cells. The authors wrote, “To create a protein modality that selectively eliminates targeted unwanted cells via engulfment, the phosphatidylserine (PtdSer)-binding domain in Protein S (ProS) was replaced with specific peptides that bind to the surface protein of targeted cells.” Once Crunch latches on, it links the target to phagocytes, which then engulf and break it down. Crunch essentially labels these unwanted cells for cell death, harnessing the power of the immune system to clear them, using a familiar process.

“In mice, we used Crunch to get rid of cancer cells that were made to express a specific cell surface protein, so we could track them,” said senior author Jun Suzuki, PhD, who led the study at iCeMS. “We also used it to eliminate certain immune cells in a model of lupus, a disease where the immune system attacks healthy tissue. In both cases, the harmful cells were successfully cleared, and signs of disease were reduced.”

The approach differs from existing therapies such as CAR T or antibody drugs. CAR T requires patient-specific cell engineering. Crunch, by contrast, is a protein that could potentially be delivered through an injection and customized for different diseases by swapping in alternative targeting sensors in the future.

“We think this could become a new kind of therapy that can be adapted to many conditions,” Suzuki added. “We can also adopt the targeting sensors from antibodies and CAR T. It’s the ecosystem for the various therapeutic tools.”

The team is now refining Crunch to improve safety, production efficiency, and clinical applicability. If successful, this strategy could open the door to a new generation of treatments that help the body clean house—removing harmful cells precisely, naturally, and on demand.