Complement C5a Fosters Tumor-promoting Immunity by Recruiting regulatory T cells in hepatocellular carcinoma

T cells, known for their tumor-killing activity, was markedly enhanced. Mechanistically, C5a was shown to promote the M2-like polarization of macrophages and the C-C-motif chemokine ligand 5 (CCL5) expression by activating the AKT signaling pathway. Further studies identified TAM-derived CCL5 as a key driver of the chemotactic activity of Tregs. Finally, blocking the C5a/C5ar1 axis synergistically enhanced the anti-tumor effects of PD-1 monoclonal antibody in both transplanted and spontaneous liver cancer mouse models. Overall, these findings reveal that cancer cell-derived anaphylatoxin C5a plays a pivotal role in promoting an inhibitory TIME in liver tumor tissues. Blocking the C5a/C5ar1 axis in combination with immune checkpoint inhibitors could represent a promising strategy for treating HCC.