Engineering aptamer-based therapeutics for precision cancer immunotherapy: from molecular targeting to clinical applications

Although cancer immunotherapy has revolutionized cancer therapy, the clinical efficacy of this approach is restricted due to tumor heterogeneity, immune escape, therapeutic resistance, poor tumor penetration, and toxic side effects. Short single-stranded DNA or RNA oligonucleotides, termed aptamers, have high affinity for a given target, low immunogenicity, and high chemical programmability and are emerging as promising agents for precision cancer therapies and immuno-oncology. This review aims to provide a comprehensive, integrated overview of the development of aptamer-based cancer therapeutics, from molecular engineering and pharmacology to clinical applications and translational potential. The discovery and optimization of tumor and immune-specific aptamers have been enhanced by the development of conventional SELEX, Cell-SELEX, in vivo SELEX, high-throughput sequencing, microfluidic selection, and AI-assisted selection. To enhance nuclease resistance, circulation time, biodistribution, and tumor accumulation, chemical modifications such as PEGylation, 2′-fluoro, 2′-O-methyl, LNAs, phosphorothioate linkages, circularization, and lipid/albumin binding have been developed. Aptamers can directly regulate oncogenic and immune signaling pathways or be used as targeted delivery vehicles for chemotherapeutic drugs, siRNAs, miRNAs, proteins, peptides, and CRISPR-based systems. Moreover, aptamers targeting tumor-associated biomarkers, cancer stem cells, the tumor vasculature, stromal components, and immune regulatory pathways have the potential to selectively remodel the tumor microenvironment. In addition, they are well-suited to other immunotherapy strategies, including immune checkpoint inhibitors, chemotherapy, radiotherapy, photodynamic or photothermal therapy, oncolytic viruses, and cancer vaccines, thereby further supporting a multifunctional, personalized treatment approach. Although there has been significant progress in pre-clinical research, several issues remain regarding pharmacokinetics, tumor penetration, off-target effects, manufacturing, long-term safety, regulatory approval, and clinical validation. Additional advancements in aptamer engineering, nanotechnology, computational design, and biomarker-directed therapy could potentially enable the development of these platforms into successful next-generation precision cancer immunotherapies.