The apolipoprotein B mRNA editing catalytic polypeptide-like 3 (APOBEC3, A3) enzyme family is a class of cytosine deaminases with seven isoforms that play a key role in innate immune defense against viral infection [1]. The target substrates of the A3 family are single-stranded DNA and RNA, and they convert cytosine to uracil by deamination (Fig. 1A) [2]. During viral infection, the A3 family exerts antiviral effects by causing instability in viral genes through mutating viral DNA or RNA, thereby inhibiting viral replication [3,4]. The new revelation that they may also cause mutations in cellular genomic DNA suggests a possible connection between the A3 family and the chronic mutations occurring in human cancers [5,6]. Nik-Zainal and colleagues analyzed mutations in 21 different breast cancer samples and revealed a localized hypermutation phenomenon known as “Kataegis,” a finding that marks the first proposed link between the A3 family of cytosine deaminase enzymes and tumorigenesis [[7], [8], [9], [10]]. Subsequent studies have consistently shown that A3 family-associated mutations are the second most frequently detected mutational signature in human cancer tissues, after mutations associated with aging [[11], [12], [13], [14]].

Unlike many mutations confined to specific cancer types, APOBEC cytidine deaminase family-associated mutations occur across multiple cancer classes [5]. Recent analysis of The Cancer Genome Atlas (TCGA) database has further confirmed that APOBEC mutational signatures are exhibited across multiple tumor types, with chronic A3-associated mutagenesis detectable in approximately 70 % of cancer lineages and 50 % of cancer gene families. APOBEC3A (A3A) and APOBEC3B (A3B) constitute predominant contributors to these mutational signatures [5,[16], [17], [18]]. Notably, as the only exclusively nuclear-localized member of the A3 family, A3B demonstrates elevated expression across diverse malignancies including breast, lung, colorectal, bladder, cervical, head and neck, and ovarian cancers [[19], [20], [21], [22], [23], [24]]. In contrast, A3A is also expressed in these cancers but at significantly lower levels. This may be due to the fact that A3B, being significantly localized to the cell nucleus, has a greater likelihood of coming into contact with chromosomal DNA, thereby triggering mutations and damage [15].

Substantial evidence correlates A3B overexpression with adverse cancer prognoses and the promotion of therapeutic resistance [[25], [26], [27], [28]]. For example, studies on lung cancer indicate that overexpression of A3B promotes resistance to EGFR inhibitors in lung cancer [27,29]. Studies on tamoxifen resistance in ER-positive breast cancer indicate that A3B plays a major role in this process [30]. These collective findings underscore the high therapeutic value of targeting A3B for drug discovery.

This review introduces the structure and biological functions of the A3B protein, as well as its role in cancer. It summarizes the A3B inhibitors reported to date, with a focus on their design strategies and biological activity. Additionally, this review addresses the limitations of current inhibitors and proposes potential future research directions, guiding the development of A3B inhibitors with enhanced selectivity and potency.