Scientists have found a hidden weakness in an aggressive form of kidney cancer that could lead to a new combination treatment. The research was published in the Proceedings of the National Academy of Sciences.

The discovery involves clear cell renal cell carcinoma, which often carries changes in a gene called VHL. The gene normally helps stop uncontrolled cell growth.

Researchers at the University of Notre Dame found that losing VHL activates a protein called HIF-2-alpha. That makes cancer cells produce large amounts of another protein, TRAIL.

TRAIL normally tells damaged cells to destroy themselves. But too much of it traps the ‘death receptors’ inside the cell, where outside treatments cannot reach them.

The team tested belzutifan, an approved kidney cancer drug that blocks HIF-2-alpha. It lowered TRAIL levels and allowed the trapped receptors to move back to the cell surface.

Adding laboratory-made TRAIL then triggered much more cancer cell death. The combination also slowed cell division in laboratory studies and mouse models.

The work was led by Professor Xin Lu. It suggests a two-pronged attack: making it harder for cancer cells to multiply while making them easier to destroy.