Enhancing STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy.

Abstract

2571 Background: Activating the innate immune pathway of stimulator of interferon genes (STING) can elicit potent anti-tumor immunity via the production of type-I interferons (IFN-I). However, cyclic-dinucleotide (CDN) STING agonists have undesirable pharmacological properties. Most CDNs in clinical development are administered intratumorally, thus precluding their applications in treating metastasis, hematologic malignancies, and hard-to-reach solid tumors. Here, we report the development of a new nanoparticle system for the systemic delivery of CDN STING agonists with potent efficacy, favorable pharmaceutical properties, and acceptable safety profiles. Methods: Nutritional metal ions play crucial roles in modulating immune pathways, which could potentially be used for enhancing STING activation. We screened different metal ions and found that manganese ion (Mn2+) achieved strong synergy with CDN STING agonists for inducing IFN-I production. We further developed a new nanoparticle system for co-delivery of Mn2+ and CDN for systemic cancer immunotherapy. Results: Mn2+ induced up to 77-fold enhancement in CDN-mediated STING activation. Mixing CDNs with Mn2+ resulted in the self-assembly of nanocrystals, and the lipid layer coating led to uniform nanoparticles. The resulting STING-activating CDN-Mn nanoparticle (SNP) given intravenously elicited IFN-I responses, attenuated the suppressive functions of myeloid cells, remodeled the immunosuppressive tumor microenvironment, and expanded CD8+ T cells for sustained tumor control. Intravenous SNP therapy resulted in robust anti-tumor efficacy in multiple murine tumor models, including a genetically engineered mouse model of MMTV-PyMT triple-negative breast cancer. We have also demonstrated the robust anti-tumor efficacy of SNP against VX2 head and neck squamous cell carcinomas (HNSCC) in New Zealand white rabbits. Mechanistically, the efficacy of intravenous SNP therapy was dependent on the host STING expression but independent of the tumor STING expression. In addition, the anti-tumor efficacy of SNP was decreased in mice lacking Ifnar1 or Ifngr1 expression in the B16F10 melanoma model, showing the crucial effects of IFN-I and IFN-II responses. Lastly, SNP was effectively uptaken by human PBMCs and elicited IFN-I responses when injected into fresh human tumor biopsies derived from HNSCC patients. Conclusions: SNP empowers highly effective systemic cancer immunotherapy via nanotechnology. It also underscores the potential of utilizing metal ions for immune-mediated disease treatment.