Targeting endosomal trafficking-mediated antigen escape to resensitize myeloma to CAR-T therapy.

CAR-T cell therapy, which involves engineering a patient's own immune cells to hunt down cancer, has transformed treatment for multiple myeloma, a blood cancer. But many patients relapse because tumor cells find ways to hide from these engineered hunters, a phenomenon called antigen escape. Antigens are the molecular flags on the surface of cancer cells that CAR-T cells are trained to recognize, and if those flags disappear, the therapy loses its target. Researchers have now uncovered a surprising reason why those flags go missing in myeloma: a metabolic enzyme called RRM2 is moonlighting as a cellular traffic cop, routing the flags away from the cell surface and into internal compartments called lysosomes, where they get destroyed.

The specific flags in question are proteins called MICA and MICB, which sit on the surface of stressed or cancerous cells and signal to a type of CAR-T therapy that uses a receptor called NKG2D. Using single-cell RNA sequencing, a technology that reads gene activity in individual cells, the team identified a common subgroup of myeloma cells with high RRM2 activity and very low levels of MICA/B on their surface. They found that RRM2 achieves this by activating a molecular switch called RAB7A, which sends MICA/B toward degradation, while simultaneously blocking another switch, RAB11, that would normally recycle those proteins back to the cell surface. The researchers then showed that treating cancer cells with low, non-toxic doses of osalmid, a clinically approved drug already known to inhibit RRM2, reversed this process. Restoring MICA/B to the cell surface allowed NKG2D CAR-T cells to recognize and kill the tumor cells far more effectively, achieving lasting remission in mouse models without burning out the immune cells in the process.