Tumor-Made C3 Complement Boosts Cancer Immunotherapy Response

A protein old enough to predate the evolution of blood circulation has been shown to play a role in how well cancer immunotherapy works. Scientists at Nagoya University found that complement C3, when made directly inside tumor tissue, helps block the buildup of immune-suppressing cells that would otherwise protect cancer from attack. Notably, C3 traveling through the bloodstream had no bearing on treatment success; only the locally produced version mattered. The findings appear in Nature Communications.

C3 is an ancient protein found even in simple organisms like sponges and jellyfish. Normally made in the liver, it circulates in blood to help fight infection, but its function when produced locally within tissue had remained unclear. Lead author Yuki Miyai, noted that the role of C3 made by cancer-associated fibroblasts surrounding tumors was previously unknown.

The team found that tumor-produced C3 keeps immunosuppressive myeloid cells from infiltrating the tumor microenvironment, giving the immune system a better opportunity to fight the cancer. Using mice, researchers separated the effects of liver-derived versus tumor-derived C3. Cutting liver C3 by 90% did not change how well an anti-PD-1 antibody, a drug that helps the immune system attack tumors, performed. But halting C3 production by tumor fibroblasts made the same drug less effective, even though blood C3 levels dropped only 9%.

Miyai further explained that immunotherapy effectiveness depended on local C3 rather than blood C3. When this local C3 breaks down, it produces a fragment called iC3b that blocks harmful myeloid cells from entering the tumor, improving the odds that immunotherapy works.

To see whether this effect could be reproduced artificially, the researchers tested a drug mimicking C3’s blocking action on myeloid cells. This restored immunotherapy effectiveness in tumors that had previously resisted treatment and extended survival in mice.

The team also examined lung cancer patient samples. Those with higher C3 levels in tissue surrounding their tumors had better outcomes and survival, with about half responding to treatment, compared with none among patients with lower tissue C3. Blood C3 levels again showed no correlation with outcomes.

Going forward, the researchers plan to study how to raise local C3 levels and determine optimal treatment timing. They suggest that further understanding of this protein could also inform other biological processes, including wound healing and inflammation management.