Abstract Background: Despite rapid advances in immunotherapy, the clinical use of potent immune-modulating agents remains constrained by systemic toxicities. Earli is developing a DNA-based immunotherapy platform that uses synthetic cancer-activated promoters (CAPs) to drive selective expression of therapeutic payloads in malignant cells, while remaining silent in normal tissues and benign lesions. DNA is delivered systemically to the tumor cells by lipid nanoparticles (LNPs). The platform also engages innate immunity via the immunostimulatory nature of DNA. This study highlights the dual mechanism of combining 1) CAP-driven expression of a potent immunostimulatory payload such as IL-12 with 2) cGAS-STING-induced innate immune activation. Methods: Naïve or tumor-bearing mice were treated with LNPs encapsulating either a DNA nanoplasmid encoding IL-12 under a cancer-activated promoter (CAP-IL-12) or a matched construct with three stop codons (Control-DNA). Mice were assessed for tumor growth inhibition, cytokines (IL-6, IL-1β, TNF-α), and IL-12 levels in tumor and serum. Results: LNP encapsulating Control-DNA increased transcript levels of STING downstream targets and triggered a transient rise in pro-inflammatory cytokines. This innate immune response resulted in a partial (i.e. non-durable) inhibition of tumor growth across multiple syngeneic tumor models and showed enhanced efficacy when combined with PD-1 checkpoint blockade. Importantly, in STING knockout mice, the anti-tumor response to the formulated Control-DNA was completely lost. In contrast, IV treatment with an LNP encapsulating CAP-IL-12 DNA led to complete and durable tumor regression. Surprisingly, although modest IL-12 protein was detectable in tumors, there were no substantial IL-12 levels measured in serum, demonstrating the platform's ability to concentrate a highly potent therapeutic at the tumor site while avoiding systemic exposure. Further, immune profiling showed both IL-12 and STING induced changes including increases in T cell and NK cell proliferation, granzyme B upregulation, and enhanced myeloid activation and antigen presentation. Importantly, the anti-tumor efficacy of CAP-IL-12 was retained in syngeneic tumors in STING knockout mice, demonstrating that cancer-specific payload expression is sufficient to drive efficacy even in the absence of adjuvant STING agonism. Our current work focuses on modulating STING agonism through LNP engineering approaches to fine-tune its activity in the tumor for a balanced therapeutic response. Conclusions: Overall, our findings highlight the dual-function nature of Earli’s DNA-LNP platform: a programmable, tumor-selective gene therapy system with built-in innate immune activation through STING agonism. The approach supports a new class of immunotherapies that combine precision and potency in a single genetic modality. Citation Format: Moataz Reda, Evan Bishop, Priyanka Balasubrahmanyam, Blaine McCarthy, Sushil Lathwal, Robby Chandra, Audrey Smith, Xiao Wu, Jesse Simons, Kim Tran, Ajda Rojc, Jayalakshmi Ramani, Suyog Shaha, Dang Dang, David Rosen, Badri Ananthanarayanan, Nadege Morisot, David Suhy. Leveraging cancer-activated gene expression and cGAS-STING activation for efficient tumor killing via a DNA-LNP delivery platform 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 262.
Reda et al. (Fri,) studied this question.