Aptamers and aptamer-drug conjugates as synthetic immune modulators for cancer immunotherapy.

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, currently available options, including immune checkpoint inhibitors and cellular therapies, remain limited due to immune-related toxicities, high costs, off-target effects, and variable patient responses. These challenges highlight the need for alternative, synthetic immune-modulating strategies with improved precision, safety, and scalability. Aptamers have recently emerged as promising synthetic immune modulators. Owing to their chemical synthesis, small size, low immunogenicity, and extensive chemical tunability, aptamers offer distinct advantages over protein-based biologics, including enhanced tissue penetration, batch-to-batch consistency, and flexible pharmacokinetic optimization. Beyond their established diagnostic applications, aptamers are being applied as therapeutic agents capable of modulating immune checkpoints, cytokine signaling, and immune cell recruitment within the tumor microenvironment. Aptamer-drug conjugates (ApDCs) also represent a powerful extension of this technology, enabling targeted delivery of cytotoxic or immunostimulatory payloads to tumors while minimizing systemic toxicity. Through this review, we aim to provide a comprehensive overview of aptamer-based immunotherapies, encompassing molecular engineering strategies, SELEX optimization, and structural design principles that underpin target specificity and functional activity. We further examine preclinical and emerging clinical progress, translational challenges related to formulation, pharmacokinetics, and regulatory considerations, and the evolving role of ApDCs in cancer treatment. Finally, we discuss future perspectives for aptamer technologies as next-generation synthetic immune modulators, with the potential to complement or surpass conventional immunotherapeutic approaches in precision oncology.