Complement factor B blockade by iptacopan drives antitumor complement-based immunomodulation in pancreatic cancer microenvironment.

Recent advanced comprehensive analyses reveal complement factors as critical regulators of cancer-immune system interactions. We previously identified that complement factor B (CFB), a key secreted component of the alternative complement pathway, is aberrantly upregulated 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. We investigated the effects of iptacopan on PDAC cell biology and the tumor immune microenvironment 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-Gal activity and p21 upregulation. 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 (Tregs) and the immunosuppressive CD8+/Foxp3+ Treg subset while enhancing CD8+ tumor-infiltrating lymphocytes, reshaping the tumor immune microenvironment. Combination therapy with immune checkpoint blockades (anti-PD-1 and anti-CTLA-4) further augmented antitumor effects, and triple therapy with gemcitabine/nab-paclitaxel yielded the greatest tumor suppression. These results demonstrate that iptacopan exerts dual antitumor effects by inducing tumor-intrinsic senescence and promoting an immunostimulatory tumor immune microenvironment. Therefore, CFB inhibition represents a promising complement-based immunomodulatory treatment for PDAC.