Complement C3 Has Another Role Inside Tumors: Local Protein Shapes Immunotherapy Outcomes

The same protein may play entirely different roles depending on whether it is in the blood or in a tumor. A team at Nagoya University in Japan found that when the complement protein C3 is produced locally by fibroblasts surrounding a tumor, it can improve the effectiveness of immune checkpoint inhibitors; C3 produced by the liver and circulating in the blood, however, did not show the same effect. The study adds a piece to the tumor-microenvironment puzzle of why some tumors resist anti-PD-1 treatment.

C3 is generally regarded as a core component of the complement system. It is produced in large quantities by the liver and travels through the bloodstream, helping identify and eliminate pathogens. However, the C3 gene evolved before the circulatory system emerged, suggesting that it may originally have functioned locally within tissues. The research team therefore asked whether C3 produced within tumors has immune functions distinct from those of C3 in the blood.

The answer came from separately manipulating the sources of C3. When researchers reduced liver-produced C3 in mice by about 90%, the effectiveness of anti-PD-1 treatment was not diminished. By contrast, when they removed C3 produced by cancer-associated fibroblasts, colorectal and lung cancer models became less likely to respond to treatment even though circulating C3 fell by only about 9%, and more M2-like macrophages with immunosuppressive characteristics accumulated within the tumors.

Mechanistic analysis showed that iC3b, a fragment formed when local C3 is broken down, can suppress the entry of myeloid cells into tumors through complement receptor 3 signaling. Without this barrier, immunosuppressive cells can more readily occupy the tumor microenvironment, weakening the anticancer response elicited by anti-PD-1 antibodies. The researchers then pharmacologically mimicked this blocking effect, restoring a response in mouse tumors that had previously resisted immunotherapy and significantly prolonging the animals’ survival.

Human data provided clues pointing in the same direction, though they are not yet conclusive. Among the lung cancer samples analyzed in the study, tumors with higher stromal C3 had fewer M2-like macrophages, as well as better treatment outcomes and survival; data released by the university showed that about half of the patients in this group responded to treatment, while no patients in the group with lower stromal C3 responded. Blood C3 concentrations could not make the same distinction, suggesting that if a biomarker is developed in the future, tumor tissue may provide more valuable information than a blood draw.

These findings do not yet prove that increasing local C3 can improve treatment efficacy in patients. The treatment experiments remain at the mouse stage, while the human component involved a correlation analysis between sample expression and clinical outcomes and still requires confirmation in larger, prospective studies. In addition, determining how to regulate this pathway only within tumors while avoiding disruption of the infection-defense function of systemic complement will be a key translational challenge. The team next plans to test methods for increasing local C3 and identify appropriate timing for combining them with immunotherapy.