APOBEC3B is a cytidine deaminase that functions as both an antiviral enzyme and a cancer-associated mutator. As an antiviral factor, APOBEC3B targets single-stranded viral DNA, converting cytosine to uracil and inducing G-to-A hypermutations that restrict replication of viruses including HIV, hepatitis B virus, and herpesviruses 12. The enzyme operates through NF-κB signaling pathways and is regulated post-transcriptionally by miR-138-5p 2. In cancer contexts, APOBEC3B contributes significantly to mutagenesis through multiple mechanisms. It regulates R-loops and promotes transcription-associated mutagenesis, binding to R-loop structures and altering their landscape genome-wide 3. While APOBEC3A is the primary driver of APOBEC3-associated mutational signatures in cancer cells, APOBEC3B can restrain APOBEC3A activity while contributing its own mutation burden 4. In breast cancer, APOBEC3B participates in complex focal amplifications through R-loop formation, contributing to genomic instability that characterizes high-risk ER+ tumors 5. The enzyme also plays dual roles in targeted therapy resistance, initially constraining EGFR-driven lung tumorigenesis but subsequently promoting therapy resistance through NF-κB-mediated upregulation 6.