Local tumor-produced complement C3 shown to boost checkpoint immunotherapy effectiveness

Scientists discovered that complement C3 generated inside tumors, rather than in the bloodstream, improves anti-PD-1 therapy and can reverse resistance in mouse models.

An evolutionarily ancient immune protein, complement C3, acts within tumors to prevent infiltration of suppressive myeloid cells, thereby strengthening checkpoint blockade such as anti-PD-1 antibodies, according to a Nagoya University study. Mouse experiments revealed that a 90% reduction of liver-derived C3 did not affect therapy success, but eliminating C3 production by cancer-associated fibroblasts reduced efficacy despite only a small drop in blood C3.

The team engineered a compound that replicates C3’s local effect, which rescued anti-PD-1 response in previously resistant tumors and significantly prolonged survival. Analysis of human lung-cancer samples showed that patients with abundant tissue-resident C3 responded to treatment at about 50 % versus none among low-C3 cases, while circulating C3 levels showed no correlation. These results point to local C3 as a potential biomarker and therapeutic target to improve immunotherapy outcomes. Future research will explore ways to increase intratumoral C3 and optimal timing for combination strategies.