Overcoming species-specific translational barriers in assessing drugs that leverage the potential of the cGAS-STING pathway

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway has emerged as a cornerstone of innate immune sensing, linking the detection of cytosolic DNA to type I interferon (IFN-I) and pro-inflammatory cytokine production. Activating this pathway shapes both innate and adaptive immune responses (Chen et al., 2016; Hopfner & Hornung, 2020). This explains why dysregulation of the cGAS-STING axis is implicated across multiple therapeutic areas, from oncology to autoimmunity or infectious diseases.

In cancer, activation of the cGAS-STING pathway within the tumor microenvironment promotes dendritic cell activation, cross-priming of tumor antigens, and cytotoxic T cell infiltration, thereby enabling effective anti-tumor immunity (Corrales et al., 2015; Woo et al., 2014). These findings have fueled the development of STING agonists, either as monotherapies or in combination with immune checkpoint inhibitors, particularly to convert “cold” tumors into immunologically responsive ones. Conversely, chronic or inappropriate activation of cGAS-STING signaling has been implicated in autoimmune and autoinflammatory diseases such as systemic lupus erythematosus and STING-associated vasculopathy with onset in infancy (SAVI), where excessive type I interferon signaling drives tissue damage (Motwani et al., 2019; Thim-Uam et al., 2020). Together, these observations highlight the pathway’s dual therapeutic potential: activation in cancer and inhibition in autoimmunity.

Species‑specific differences as a barrier to clinical translation

However, translating cGAS-STING targeted therapies into the clinic has proven challenging, largely due to pronounced species-specific differences between mouse and human cGAS and STING proteins. Several small molecule agonists and antagonists display divergent activity profiles across species. One of the most consequential interspecies differences lies in STING ligand selectivity. Murine STING is uniquely responsive to several synthetic small molecule agonists, most notably DMXAA (ASA404), which demonstrated robust anti-tumor activity in mouse models but failed in human clinical trials. This failure was later traced to the inability of DMXAA to activate human STING, whereas it directly binds to murine STING (Conlon et al., 2013). These differences limit the predictive value of conventional mouse models and underscore the need for humanized, immunocompetent in vivo systems that faithfully recapitulate human cGAS-STING biology while preserving intact immune crosstalk.

Humanized mouse models to bridge the cGAS–STING translational gap

To address this translational gap, genOway has developed a portfolio of target-specific humanized cGAS-STING mouse models based on precise knock-in strategies. The genO-hSTING mouse expresses human STING under physiological regulation in an otherwise fully immunocompetent background, enabling the in vivo evaluation of human-specific STING agonists and antagonists while avoiding confounding murine STING signaling. Complementing this model, the genO-hcGAS model expresses humanized cGAS, allowing direct assessment of compounds targeting human cGAS activity and downstream interferon responses in vivo. genOway has also integrated both human targets in the double-humanized genO-hcGAS/hSTING model, which replaces the entire murine cGAS-STING axis with its human counterparts while maintaining normal immune cell composition and function. Furthermore, the genO-BRGSF-HIS mouse model which contains a human-like immune system and develops functional human lymphoid and myeloid compartments is also a useful tool for studying therapeutics targeting this pathway, as previously demonstrated (Martin et al., 2025; Ren et al., 2025).

These models offer a unique platform to study the full human cGAS-STING signaling cascade in cancer, autoimmunity, inflammation and infectious diseases, enabling robust efficacy, mechanism of action, and safety assessments of human-specific therapeutic candidates.

In conclusion, as the cGAS-STING pathway continues to gain traction as a therapeutic target across diverse disease areas, predictive preclinical models are essential to guide successful clinical translation. By combining precise humanization, physiological expression, and immunocompetence, genOway’s cGAS-STING mouse models provide researchers with valuable tools to overcome species barriers and accelerate the development of next generation innate immune modulators.

‍

References

• Chen, Q., Sun, L., & Chen, Z. J. (2016). Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nature Immunology, 17, 1142–1149.
• Corrales, L., et al. (2015). Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Reports, 11, 1018–1030.
• Conlon, J., et al. (2013). Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid. The Journal of Immunology, 190, 5216–5225.
• Hopfner, K. P., & Hornung, V. (2020). Molecular mechanisms and cellular functions of cGAS–STING signalling. Nature Reviews Molecular Cell Biology, 21, 501–521.
• Martin, G., et al. (2025). Tumor-dependent myeloid and lymphoid cell recruitment in genO-BRGSF-HIS mice: a novel tool for evaluating immunotherapies. Frontiers in Immunology, 16:1624724.
• Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019). DNA sensing by the cGAS–STING pathway in health and disease. Nature Reviews Genetics, 20, 657–674.
• Ren, M. et al. (2025). cGAS-STING signaling in the tumor microenvironment induces myeloid cell activation and favors T cell-mediated antitumor immunity. Cancer Biology & Therapy, 26(1): 2585562
• Sun, L., et al. (2013). Cyclic GMP–AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 339, 786–791.
• Thim-Uam, A., et al. (2020). STING Mediates Lupus via the Activation of Conventional Dendritic Cell Maturation and Plasmacytoid Dendritic Cell Differentiation. iScience, 23(9):101530.
• Woo, S. R., et al. (2014). STING dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity, 41, 830–842.

‍