Nagoya team links local complement C3 in tumors to stronger immunotherapy response

SciTechDaily reported that researchers at Nagoya University found complement protein C3 helps keep immunosuppressive cells out of tumors only when it is produced inside the tumor, work published in Nature Communications. C3 is an ancient immune protein; the liver makes most circulating C3 that fights infection in blood. Lead author Yuki Miyai and colleagues focused instead on C3 made by cancer-associated fibroblasts around tumors. Local tumor C3 was tied to fewer immunosuppressive myeloid cells in the tumor microenvironment and better immunotherapy outcomes, while bloodstream C3 showed no connection to treatment response. In mice, cutting liver-derived C3 by 90% did not weaken anti-PD-1 antibody effects. Blocking fibroblast C3 production inside tumors made the same immunotherapy less effective even though blood C3 fell by only 9%. Miyai said local C3 breaks down into a fragment called iC3b that stops harmful myeloid cells from entering the tumor. The team also tested whether recreating the local effect could help tumors that make too little C3, aiming to support immunotherapy in resistant cancers. SciTechDaily said the findings point to tumor-site C3 activity, not circulating levels, as the relevant lever for response. Implication: Tumor-local C3 biology gives drug developers a distinct target from blood-based complement for overcoming immunotherapy resistance.