Alternative polyadenylation in cancer: mechanisms, functions, and therapeutic potential

Alternative polyadenylation (APA) is a pervasive post-transcriptional regulatory mechanism that generates transcript isoforms with distinct 3' untranslated regions, terminal exons, or coding potential, thereby influencing mRNA stability, translation, localization, and protein output. Rather than representing a uniform 3'UTR-shortening process, APA comprises heterogeneous 3'-end regulatory events, including tandem 3'UTR APA and upstream APA events such as intronic polyadenylation (IPA), which differ in mechanisms, detection strategies, functional consequences, and clinical interpretation. Dysregulated APA is increasingly recognized as an important contributor to cancer initiation and progression. Tandem 3'UTR APA can remove miRNA- or RNA-binding protein-mediated repression and enhance oncogenic transcript output, whereas upstream APA events, including IPA, can generate prematurely terminated RNAs, truncated proteins, soluble isoforms, or neoantigenic products. In this review, we summarize the classification and biological consequences of major APA events, as well as experimental and computational approaches for APA analysis. We then discuss regulatory mechanisms involving core 3'-end processing factors, RNA-binding proteins, splicing-polyadenylation coupling in upstream APA/IPA, transcription-associated regulation, and promoter-terminator communication. Functionally, aberrant APA contributes to proliferation, invasion and metastasis, metabolic reprogramming, tumor microenvironment remodeling, antitumor immunity, and immune escape. Finally, we highlight APA events, APA regulators, 3'UTR-based signatures, and upstream APA/IPA-derived products as emerging biomarkers and discuss small-molecule, RNA-based, and CRISPR-based strategies for targeting APA or 3'-end processing in cancer.