Checkpoint drugs taught the immune system to fight cancer — but they reach only a fraction of tumors. Here’s the target researchers think could change that.
Older treatments like chemotherapy attack any fast-dividing cell, which is why they hit healthy tissue and cause such harsh side effects. Immunotherapy takes a different route: rather than poisoning the tumor directly, it removes the brakes that keep the immune system from recognizing cancer as a threat.
Many tumors display a surface protein, PD-L1, that signals passing immune cells to stand down. Drugs such as Keytruda and Opdivo block that handshake, freeing T-cells to recognize and destroy the cancer — and they are generally far better tolerated than chemotherapy or radiation.
The PD-L1 escape hatch is only used by about one in five solid tumors. The other ~80% evade the immune system through different mechanisms, so checkpoint inhibitors simply pass them by.
ENPP1 is an enzyme that, when over-expressed, degrades cGAMP — a molecular “alarm” cells use to flag the immune system that something has gone wrong. Tumors that crank up ENPP1 effectively silence that alarm and grow unnoticed. Researchers estimate roughly half of solid tumors lean on this trick.
By blocking ENPP1 activity, CY-3132 transforms tumor cells from immune evading to immune activating.— Dr. Shoshana Shendelman, CEO, Cyana Therapeutics
One company pursuing this approach is Cyana Therapeutics, led by Dr. Shoshana Shendelman, whose published research spans molecular medicine and rare disease. You can follow her work at drshendelman.com or on X.