Local tumor C3, not blood C3, drives immunotherapy response in Nagoya study

ScienceDaily reported that Nagoya University scientists found complement protein C3 improves cancer immunotherapy only when it is produced locally in tumor tissue, not when it arrives through the bloodstream, according to a Nature Communications study. Most C3 is made in the liver and circulates to fight infection. Lead author Yuki Miyai said the role of C3 from cancer-associated fibroblasts inside tumors had been unclear. In mouse experiments, cutting liver-produced C3 by 90% left an anti-PD-1 immunotherapy drug as effective as in normal mice. Stopping fibroblasts inside the tumor from making C3 made the same treatment less effective even though circulating C3 fell by only about 9%. Miyai said a breakdown fragment called iC3b stops harmful myeloid cells from entering the tumor, making immunotherapy more likely to work. A drug designed to imitate that local blocking effect allowed immunotherapy to work against previously resistant tumors and significantly extended survival in mice. In lung cancer patient samples, about half of patients with high local C3 around tumor cells responded to treatment, while none with lower local levels responded. Blood C3 levels were not linked to success. The team plans to test ways to raise C3 inside tumors and the best treatment timing.