Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.

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