Aptamers in cancer therapy: Why has clinical translation lagged behind preclinical promise?

Aptamers have attracted substantial interest as cancer therapeutics due to their high target specificity, chemical programmability, and versatility in drug and RNA delivery; however, despite extensive preclinical development, clinical translation in oncology has remained extremely limited, with no aptamer-based therapies approved for cancer indications to date. This gap reflects not a failure of binding affinity, but a fundamental misalignment between aptamer selection and evaluation paradigms and the biological complexity of human tumors. Most aptamers are selected against purified proteins or homogeneous cell lines that fail to capture tumor heterogeneity, dynamic target regulation, and microenvironmental influences encountered in patients, while inconsistent assessment of pharmacokinetics, biodistribution, and functional activity further limits translational predictability. Through analysis of representative clinical programs, including the systemic nucleolin-targeting aptamer AS1411, the microenvironment-modulating CXCL12 inhibitor NOX-A12, and the locally administered personalized platform AM003, this review highlights how delivery strategy, target context, and clinical deployment critically shape therapeutic outcomes. Recurrent translational barriers related to systemic exposure, tumor accessibility, regulatory pathways, and competition with established modalities are identified, together with lessons from both failed and emerging programs. Finally, we discuss practical strategies to improve clinical alignment, including human-relevant selection models, localized or combination therapies, and AI-assisted design, positioning aptamers for context-appropriate roles in future precision oncology.