Complement factor B deficiency promotes lung cancer progression via FOS-mediated tryptophan metabolism and immune suppression

BACKGROUND: Complement Factor B (CFB) is a component of the alternative complement pathway with emerging roles in cancer biology. This study investigated the role of CFB in lung cancer progression and characterized its downstream molecular and immunological effects. METHODS: We performed transcriptomic analysis of CFB-silenced lung adenocarcinoma cells and validated findings in clinical specimens. CFB deficiency was assessed using in vitro functional assays, metabolite measurements, and T cell coculture systems. Immunomodulatory effects were evaluated in vivo using tumor models treated with an indoleamine 2,3-dioxygenase (IDO) inhibitor. RESULTS: CFB silencing activates a proto-oncogene C-Fos (FOS)-dependent upregulation of tryptophan metabolism enzymes. CFB expression inversely correlates with FOS and tryptophan metabolic enzymes in human lung cancer specimens, with stronger alterations in advanced disease. Mechanistically, CFB deficiency enhances tryptophan catabolism to kynurenine, promoting regulatory T cell activation through aryl hydrocarbon receptor (AhR) signaling while suppressing CD8 + T cell function. In vivo, CFB-knockdown tumors show accelerated growth, enhanced immune suppression, and increased tryptophan catabolism. These effects are reversed by IDO inhibitor treatment. CONCLUSION: We identify a CFB-FOS-IDO axis that regulates tryptophan metabolism and shapes the tumor immune microenvironment in lung cancer. CFB deficiency promotes tumor progression by enhancing tryptophan catabolism, resulting in an immunosuppressive microenvironment. These findings reveal potential therapeutic targets to overcome immune evasion in lung cancer.