Cancer Research · asia
Immunotherapy Success Depends on More Than Tumor Cells: Why Local Complement C3 May Shape Treatment Efficacy
Studies in mice and lung cancer specimens indicate that complement C3 produced by tumor fibroblasts can prevent immunosuppressive myeloid cells from entering tumors and is associated with a better anti-PD-1 response; C3 in the blood, however, does not have the same effect.
Immune checkpoint inhibitors can release the “brakes” on immune cells, but they are effective in only some patients. A Nagoya University team has now traced this difference to a group of fibroblasts surrounding tumors that are often regarded as supporting players: the complement C3 they produce locally may determine whether immunosuppressive cells can flood into tumors, thereby affecting whether anti-PD-1 treatment works.
C3 is normally produced in large quantities by liver cells and circulates in the blood to help defend against infection. Through mouse experiments, the researchers separated the effects of the two sources: reducing liver-produced C3 by about 90% did not weaken the efficacy of anti-PD-1 treatment; however, specifically removing C3 from cancer-associated fibroblasts caused circulating C3 to fall by only about 9%, yet colorectal cancer and lung cancer models became resistant to treatment.
The key appears to lie not in C3 itself, but in its breakdown product iC3b. The study showed that iC3b can transmit signals through complement receptor 3 to suppress myeloid cell infiltration. After this local barrier was lost, M2-like macrophages with immunosuppressive characteristics increased, suppressing the antitumor immune response that should otherwise have been reactivated.
This mechanism also provides a therapeutic lead. In mouse tumors that initially did not respond to immunotherapy, the team used a drug to mimic the C3 pathway’s suppression of myeloid cell infiltration, restoring the tumors’ sensitivity to PD-1 blockade and extending mouse survival. This remains an animal-stage proof of concept and cannot yet demonstrate that increasing C3 within patients’ tumors, or directly activating complement receptor 3, would provide safe and durable clinical benefits.
Human data offered preliminary support. After analyzing lung cancer tumor specimens, the researchers found that tumors with higher stromal C3 had fewer M2-like macrophages and also showed better immunotherapy outcomes and survival. According to data released by the university, about half of the patients in the high-stromal-C3 group responded to treatment, while no patients in the low-C3 group responded. By contrast, blood C3 concentrations showed no clear association with treatment efficacy, suggesting that if a biomarker is to be developed, tumor tissue may provide more useful information than a blood test.
However, the human findings currently show mainly correlations. The number of patients, cancer types, and treatment conditions still limit the generalizability of the results, and it cannot be ruled out that high C3 is merely an accompanying feature of a more favorable tumor microenvironment. The paper was also published as an early version that has not yet completed editing. In addition to broader clinical validation, the next steps will require clarifying how to select patients, when to intervene, and whether locally modulating complement could introduce risks of infection, inflammation, or other unintended immune effects.