Ancient molecule made inside tumors drives immune response, study finds

Inside tumors in Nagoya, Japan, scientists have discovered a tiny molecule that helps some cancer treatments work better — and it dates back to creatures without blood vessels, like sponges and jellyfish.

Researchers at Nagoya University found that a protein called complement C3, when made inside a tumor, helps the immune system fight cancer. But here's the surprising part: the same protein floating in the blood did nothing to improve treatment. Only the C3 produced right inside the tumor mattered.

The team, led by Assistant Professor Yuki Miyai from Nagoya University's Graduate School of Medicine, wanted to understand why some cancers respond to immunotherapy — treatments that help the immune system attack tumors — while others do not.

The answer came from separating two sources of C3. The liver makes most of the C3 in our blood, where it helps fight infections. But tumors are also surrounded by normal cells called fibroblasts that can make their own C3 locally.

When researchers reduced liver-produced C3 in mice by 90 percent, immunotherapy still worked perfectly. But when they stopped fibroblasts inside the tumor from making C3, immunotherapy became less effective — even though blood C3 barely changed, dropping only 9 percent.

"What determined the efficacy of the immunotherapy treatment was not the C3 in the blood, but the local C3 produced at the tumor site," Miyai explained. When local C3 breaks down, it forms a fragment called iC3b that blocks harmful immune cells from entering the tumor, giving treatment a better chance to work.

The finding could help patients whose tumors resist immunotherapy. When researchers gave mice a drug that mimicked C3's blocking effect, immunotherapy succeeded in tumors that had previously resisted treatment, and mice lived significantly longer.

The results also help predict which patients might benefit. In lung cancer patients, about half with high C3 levels in tumor tissue responded to immunotherapy, compared with none of those with lower levels. Again, blood C3 levels made no difference.

The team now plans to test ways to boost local C3 production and find the best timing for treatment. They also believe understanding this ancient protein could illuminate other processes, like how bodies heal wounds and manage inflammation.

The findings were published in Nature Communications.