A protein that predates the evolution of the human circulatory system could hold an unexpected key to improving cancer immunotherapy.

Researchers at Japan’s Nagoya University found that complement C3 can help immunotherapy work more effectively when the protein is produced inside a tumor. The finding could offer a new strategy for treating cancers that have developed resistance to immune-based therapies.

The study, published in Nature Communications, suggests that where C3 is produced may matter more than how much of the protein is circulating through the bloodstream.

C3 is far older than humans

Complement C3 is part of the immune system and is considered evolutionarily ancient. Versions of the protein are found in organisms as simple as sponges and jellyfish, long before the development of the human circulatory system.

In humans, most C3 is produced by the liver and released into the bloodstream, where it helps the immune system respond to infections.

But researchers have now identified a different role for C3 when it is produced locally within tumor tissue.

“Cancer tumors are surrounded by normal cells called fibroblasts,” said Yuki Miyai, assistant professor at Nagoya University and lead author of the study. The researchers investigated what happens when these cancer-associated fibroblasts produce C3 within the tumor.

Local C3 helps clear the way for immune cells

Cancer tumors can create an environment that suppresses the immune system, making it harder for treatments such as immune checkpoint inhibitors to work.

The Nagoya University team found that C3 produced inside tumors can prevent certain immunosuppressive myeloid cells from accumulating there. These cells can interfere with the immune system’s ability to attack cancer.

The researchers found that when local C3 breaks down, it produces a fragment called iC3b. This appears to prevent harmful myeloid cells from infiltrating the tumor, allowing cancer-fighting immune responses to function more effectively.

The distinction between local and circulating C3 was particularly striking.

Bloodstream C3 did not determine treatment success

In experiments involving mice, researchers reduced liver-produced C3 by 90%. Despite the dramatic reduction in circulating C3, treatment with an anti-PD-1 immunotherapy remained about as effective as it was in mice with normal C3 levels.

The results changed when researchers prevented fibroblasts inside tumors from producing C3.

Although this caused only a 9% reduction in circulating C3, the immunotherapy became significantly less effective.

That suggested the crucial factor was not the amount of C3 in the blood, but the amount being produced at the tumor site.

Researchers managed to overcome resistant tumors

The team then asked whether the C3 mechanism could be recreated in tumors that normally resist immunotherapy.

They tested a drug designed to mimic the way C3 prevents immunosuppressive myeloid cells from entering tumors.

In mice, the approach helped immunotherapy work against tumors that had previously resisted treatment and significantly extended survival.

The finding does not mean the approach is ready for use in patients. The experiments were primarily conducted in animal models, and additional research will be needed to determine whether the same strategy is safe and effective in humans.

Lung cancer samples offered another clue

The researchers also examined tumor samples from people with lung cancer.

Patients with higher levels of C3 in tissue surrounding their tumors generally had better treatment outcomes and longer survival. About half of the patients with high local C3 levels responded to treatment, while none of those with lower levels did.

Once again, C3 levels in the bloodstream did not show the same relationship with treatment response.

This raises the possibility that measuring C3 within tumor tissue could eventually help researchers identify patients who are more likely to benefit from certain immunotherapies.

A potential new route around immunotherapy resistance

Cancer immunotherapy has transformed treatment for some patients, but tumors can resist these therapies by creating an environment that prevents immune cells from mounting an effective attack. The new research points to the tumor’s surrounding environment as an important part of that problem.

Rather than simply increasing C3 throughout the body, future treatments might focus on increasing or activating C3 specifically inside tumors. Researchers at Nagoya University say their next steps include finding ways to increase local C3 and determining the best timing for such treatments.

The work could also have implications beyond cancer, since local C3 activity may play a role in processes such as wound healing and inflammation.

For now, the discovery offers an intriguing lesson in cancer biology: sometimes, the location of an immune molecule may matter just as much as the molecule itself.