An ancient molecule that existed long before the evolution of blood circulation systems has been found to support cancer immunotherapy. Researchers at Nagoya University in Japan found that the complement C3 protein acts within tumors to prevent the accumulation of immunosuppressive cells, but only when produced within the tumor. C3 circulating in the blood did not affect treatment results. Published in nature communicationsthe findings suggest that replicating this effect artificially could help patients with tumors that don’t naturally produce enough of this protein.
The C3 protein is evolutionarily very old and is present in simple organisms such as sponges and jellyfish. It is primarily produced in the liver and travels through the blood to protect against infections and plays an important role in the body’s immune system. However, its role when produced locally in tissues and organs is largely unknown.
Cancer tumors are surrounded by normal cells called fibroblasts. Until now, the role of complement C3 produced by these cancer-associated fibroblasts within tumor tissues was unknown. ”
Yuki Miyai First author, Assistant Professor, Nagoya University Graduate School of Medicine
Researchers found that C3 produced in tumor tissue impedes the infiltration of immunosuppressive myeloid cells into the tumor microenvironment. This increases the chances that your body’s immune defenses will fight cancer. The results identified C3 as a new factor that controls the effectiveness of cancer immunotherapy, a cancer treatment that helps the immune system recognize and attack cancer cells.
To find out whether C3 in the blood also plays a role in the effectiveness of immunotherapy, the research team used mice to separate the role of C3 according to its source. When C3 produced in the liver was reduced by 90%, drugs that help the immune system attack tumors (anti-PD-1 antibodies) were as effective as in mice with normal C3 levels.
However, when C3 production by fibroblasts within the tumor was stopped, the same drug became less effective, even though circulating C3 in the blood remained largely unchanged (9% reduction).
“What determined the effectiveness of the immunotherapy treatment was not C3 in the blood, but local C3 produced at the tumor site. When this C3 is destroyed, a fragment called iC3b is formed, which blocks harmful bone marrow cells from entering the tumor. As a result, the immunotherapy is more likely to be effective,” Professor Miyai explained.
To test whether replicating the effects of C3 would be effective in cancers that don’t respond to immunotherapy, the researchers tested drugs that mimic C3’s blocking effects on bone marrow cells. This enabled immunotherapy to be effective against tumors that had previously been resistant to treatment, significantly extending the survival time of the mice. The results could help doctors predict which patients will benefit from immunotherapy and provide new options for cancers that initially do not respond to immunotherapy.
Tumor samples from lung cancer patients were also analyzed. Patients with higher C3 levels in the tissue surrounding cancer cells had better treatment outcomes and survival rates. About half responded, but none of the patients had low C3 levels. Again, there was no difference in blood C3 levels.
Next, the researchers will conduct experiments to increase local C3 levels and identify the best timing for treatment. The authors believe that understanding how this protein functions could shed light on other biological processes, such as how the body heals wounds and manages inflammation.
sauce:
Reference magazines:
Yuya Miyai others. (2026). Local but non-circulating complement C3 forms an immune checkpoint inhibitory effect by regulating myeloid cell infiltration. nature communications. DOI: 10.1038/s41467-026-75542-3. https://www.nature.com/articles/s41467-026-75542-3
