Complement Factor B Blockade by Iptacopan Drives Antitumor Complement-Based Immunomodulation in Pancreatic Cancer Microenvironment.

Abstract

Recent advanced comprehensive analyses reveal complement factors as critical regulators of cancer-immune system interactions. It was previously identified that complement factor B (CFB), a key secreted component of the alternative complement pathway, is aberrantly up-regulated in pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression. Iptacopan (LNP023), a selective CFB inhibitor, has established efficacy in complement-mediated disorders; however, its anticancer potential remains unexplored. The effects of iptacopan on PDAC cell biology and the tumor immune microenvironment were investigated using in vitro assays and orthotopic mouse models. Iptacopan significantly suppressed human and murine PDAC cell proliferation and enhanced gemcitabine cytotoxicity. Mechanistically, CFB inhibition induced senescence, as evidenced by increased senescence-associated β-galactosidase activity and p21 up-regulation. In in vivo preclinical studies, iptacopan reduced tumor growth, diminished intratumoral CFB and C5b-9 deposition, and increased p21 expression, indicating tumor-localized complement inhibition. Furthermore, iptacopan decreased conventional Foxp3⁺ regulatory T cells and the immunosuppressive CD8⁺/Foxp3⁺ regulatory T-cell subset while enhancing CD8⁺ tumor-infiltrating lymphocytes, reshaping the tumor immune microenvironment. Combination therapy with immune checkpoint blockades (anti-programmed death-1 and anti-cytotoxic T-lymphocyte-associated protein 4) further augmented antitumor effects, and triple therapy with gemcitabine/nab-paclitaxel yielded the greatest tumor suppression. These results show that iptacopan exerts dual antitumor effects by inducing tumor-intrinsic senescence and promoting an immunostimulatory tumor immune microenvironment. CFB inhibition therefore represents a promising complement-based immunomodulatory treatment for PDAC.