Programmable Immunity: DNA Nanostructures in Cancer Immunotherapy

Despite significant progress in cancer immunotherapy, challenges such as limited immune activation, tumor immune evasion, low response rates in solid tumors and off-target effects continue to hinder therapeutic efficacy. These challenges necessitate strategies to remodel the immune-suppressive tumor microenvironment (TME) into an immune activated state. Over the past decade, nanotechnology-based cancer immunotherapies have gained considerable attention for their ability to modulate the TME and stimulate immune responses. Among these, DNA nanotechnology-based systems have emerged as highly promising candidates due to their inherent immunomodulatory, biodegradable, and biocompatible properties. This review discusses recent advances in DNA nanostructures including tetrahedrons, nanotubes, nanocages, spherical nucleic acids (SNAs), DNA hybrid nanomaterials and DNA/RNA hybrids, highlighting their immunotherapeutic mechanisms and potential to enhance cellular uptake, immune cell targeting and activation of key pathways. Preclinical studies demonstrate that DNA nanostructures such as DNA tetrahedrons can induce immunogenic cell death, endoplasmic reticulum stress, and dendritic cell maturation, while DNA nanovaccines and CpG-functionalized DNA origami activate TLR9 and STING pathways to enhance cytotoxic T lymphocyte (CTL) and antigen-presenting cell (APC) responses. Furthermore, DNA hydrogels and DNA-metal hybrids enable controlled drug delivery and immune stimulation. In this review, different DNA-based nanostructures have been discussed with their immunotherapeutic mechanism, emphasizing their potential to transform immune modulation strategies and overcome the challenges associated with conventional cancer therapies. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures.