Local, but not circulating, complement C3 shapes immune checkpoint blockade efficacy by controlling myeloid cell infiltration

The roles of circulating complement C3, produced in hepatocytes, in immune defense have been extensively studied. Interestingly, the C3 gene evolved before the circulatory system, suggesting an essential but yet undefined role of locally produced C3. Here, we investigate the effect of C3 on cancer immunotherapy and find that cancer-associated fibroblast (CAF)-derived C3, not systemic, hepatocyte-derived C3, influences the efficacy of immune checkpoint blockade (ICB). Colorectal and lung tumors developed in CAF-specific C3 knockout mice exhibit resistance to anti-PD-1 therapy, with increased immunosuppressive M2-like macrophage infiltration. Mechanistically, the C3 degradation product iC3b suppresses myeloid cell infiltration via complement receptor 3 signaling. Moreover, therapeutic targeting of this pathway restores sensitivity to PD-1 blockade therapy in immunotherapy-resistant mouse tumors. In human cancers, stromal C3 expression correlates with reduced M2-like macrophage infiltration and improved immunotherapeutic outcomes. Thus, our data demonstrate the role of locally produced C3 in the innate immune response, which may have been conserved across many organisms.