Abstract 2404: Selective tumor immune activation by novel nucleic acid drug.

Abstract Introduction: Cancer-selective immune activation by artificial nucleic acids holds promise as a potent therapeutic modality for cancer treatment. We developed a hairpin DNA self-assembly technology and found it effectively suppresses tumor growth. Specifically, our developed compound TKG-002 activated cellular innate immunity and demonstrated potent tumor growth inhibition. Here, we discuss the results of tumor growth suppression by TKG-002. Experimental Design: Two hairpin DNA sequences (oHP) were designed. Among these, the oHP showing the strongest cancer growth suppression effect in B16 tumor-bearing mice was selected and named TKG-002. In vitro tests confirmed TKG-002's self-assembly triggered by binding to miR-21. We also investigated the induction of innate immune activation that causes cancer growth suppression. Results: TKG-002 was confirmed to aggregate under conditions of abundant miR-21 expression, forming long double-stranded DNA to which cGAS binds. Administration of TKG-002 to cancer cells induced apoptosis via the cGAS-STING pathway, including the production of phosphorylated IRF3. When TKG-002 was administered intra-tumorally to B16-bearing mice using an appropriate DDS, tumor growth was strongly suppressed. Aggregates of CD8+ T cells and CD4+ T cells were observed at the periphery of the shrinking tumor tissue. While TKG-002 alone demonstrated sufficient tumor growth suppression, combination with anti-PD-1 antibody resulted in even greater tumor growth inhibition. Conclusions: The suppression of miR-21-overexpressing cancer growth by TKG-002 represents a potent therapeutic modality enabling selective tumor lysis through intracellular DNA self-assembly. The engineered TKG-002 induced autoimmunity toward targeted tumor lysis by forming long double-stranded DNA via miR-21. Further safety evaluation and condition optimization of TKG-002 are expected to establish it as an efficient cancer treatment modality. Citation Format: Akimitsu Okamoto, Kunihiko Morihiro, Makoto Yamamoto. Selective tumor immune activation by novel nucleic acid drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2404.