Stanford Medicine researchers announced on Mar. 24 a new method that could help immune cells find and attack solid tumors, addressing a major challenge in cancer immunotherapy.
This approach is significant because it may allow for more effective treatment of cancers that have been difficult to target with existing therapies. Solid tumors have proven resistant to some forms of immunotherapy, such as CAR-T cell therapy, which has been successful in treating blood cancers but less so with solid masses.
The new technique involves equipping certain immune cells with surface proteins that can detect metabolic byproducts released by cancer cells. These engineered cells are then able to migrate toward the tumor site and infiltrate the mass. "We found that when we equip immune cells with receptors that sense metabolites released by cancer cells, they can sense the tumor, migrate toward it, infiltrate it and control tumor growth, which markedly enhances the survival of mice with human breast and ovarian cancers," said Livnat Jerby, PhD, assistant professor of genetics at Stanford Medicine.
Jerby explained that traditional CAR-T therapies focus on targeting proteins on the surface of cancer cells. In contrast, this new method enables immune cells to follow chemical trails left by tumors in their environment. The research team used CRISPR technology to identify genes in natural killer (NK) cells responsible for this migration ability and tested these modified NK cells in mice bearing human breast or ovarian cancers.
"Surprisingly, we didn't see many chemokine receptors among the winners," Jerby said about their gene screening process. Instead, they found receptors—termed tumor-homing GPRs (thGPRs)—that recognize chemoattracting metabolites like phospholipids and fatty acids produced by rapidly growing cancer cells.
Focusing on one receptor called GPR183—which detects oxidized cholesterol—the team demonstrated improved migration and tumor-killing abilities when engineering T or NK cells to express this protein. "We saw a more than doubling in the number of complete responses in the animals," Jerby said.
The researchers are now exploring ways to further enhance these engineered receptors for clinical use and plan future trials using GPR183-modified immune cells. "To the best of our knowledge, no one has tried to use cancer metabolism...to attract cancer-killing immune cells to the tumor," Jerby said. "But our study uncovered the potential of this approach, and the results are quite promising."
