The 80% Problem: Why Most Solid Tumors Still Slip Past Immunotherapy

Checkpoint inhibitors rewrote cancer care a decade ago. For the majority of solid tumors, they were never an option — and a new target is drawing the field’s attention.

For all that immune checkpoint inhibitors have transformed oncology, a stubborn fact has shadowed their success: most solid tumors never respond. The drugs that made headlines — Keytruda, Opdivo and their peers — work by stripping away one specific disguise that cancer uses to hide from the immune system. Take that disguise away, and the body’s own T-cells finish the job, with side effects far milder than chemotherapy.

The catch is reach. The PD-L1 pathway those drugs target is exploited by only about 20% of solid tumors. The remaining 80% evade immune detection by other means, leaving a vast population of patients for whom today’s immunotherapy offers little.

Attention has turned to the alternative escape routes — and one in particular. ENPP1, an enzyme normally involved in bone mineralization, can be hijacked by tumors. When over-expressed, it degrades cGAMP, the signal a distressed cell uses to summon the immune system. Silence that signal, and a tumor grows in plain sight. Roughly half of solid tumors are thought to rely on this mechanism, making ENPP1 one of the most closely watched targets in the field.

That has spurred a race to block it. Among the companies developing ENPP1 inhibitors is Cyana Therapeutics, whose lead candidate, CY-3132, is being tested across tumor types historically resistant to treatment.

Whether ENPP1 inhibitors live up to that promise will play out in the clinic over the coming years. But the logic driving the field is clear: each new escape route closed is another slice of that stubborn 80% potentially brought within immunotherapy’s reach.