Carrimycin suppresses the TCF3-BCR signaling axis and induces oxidative DNA damage in Burkitt lymphoma

Abstract Burkitt lymphoma (BL) is a highly aggressive B-cell malignancy with poor outcomes in relapsed or central nervous system (CNS)-involved cases. This study investigates the antitumor mechanism of Carrimycin, a genetically engineered macrolide antibiotic, in BL. In vitro assays demonstrated that Carrimycin exerts potent, dose-dependent cytotoxicity, inducing G0/G1 cell cycle arrest and caspase-dependent apoptosis. Mechanistically, it triggered the generation of reactive oxygen species (ROS), leading to DNA damage. Transcriptomic profiling and molecular assays revealed that Carrimycin binds to the transcription factor 3 (TCF3), causing a collapse of the tonic B-cell receptor (BCR) signaling pathway. Genetic knockdown of TCF3 partially rescued BL cells from Carrimycin-induced cytotoxicity, confirming this molecular dependency. In vivo, Carrimycin suppressed tumor burden and prolonged survival in both subcutaneous and intracranial models with a favorable safety profile. In conclusion, Carrimycin is a therapeutic agent that targets TCF3 to inhibit the tonic BCR signaling axis while simultaneously driving lethal oxidative stress. Its systemic and intracranial efficacy positions Carrimycin as a highly promising candidate for clinical translation in high-risk and CNS-involved BL.