Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity

Abstract

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STINGR284S into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STINGR284S mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically “cold” tumors that are refractory to current therapies.

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection

“…As expected, in HDF-inRFP and -inALTO cells, diABZI treatment led to a substantial activation of STING and downstream signaling as indicated by TBK1 S172 autophosphorylation and phosphorylation of STING S366 , IRF3 S386 , and the NF-κB subunit p65 S536 (Fig 2A, lanes 2 and 6). STING phosphorylation is required for its trafficking and subsequent ubiquitination and degradation [37, 38]. Consistently, we observed a sharp reduction of STING protein level in diABZI- treated cells (Fig 2A, left panel, lanes 2 and 6).…”

“…Therefore, it is likely that ALTO-induced TBK1 S172 autophosphorylation stimulated its degradation, thereby reducing the amount of TBK1 available for STING phosphorylation. Because STING phosphorylation triggers its degradation [37, 38], the lack of STING phosphorylation could inhibit its degradation and cause the observed accumulation of STING in the ALTO-expressing cells.…”

Sniping Cancer Stem Cells with Nanomaterials

“…259,260 Recently, many stable and effective mRNA packaging nanotechnologies have been developed to protect mRNAs from degradation by RNA enzymes and to efficiently deliver mRNAs into target cells. 261,262 Peŕez-Nuńẽz et al targeted CSCs in TNBC for low expression of ligand-dependent coinhibitory factor (LCOR), which promotes tumor immune escape, and combined the use of extracellular vesicle-delivered LCOR mRNAs with a PD-L1 inhibitor, which was able to overcome drug resistance in TNBC and eradicate the cancer in preclinical model (Figure 6D). 263 The application of mRNA therapy to CAR-T therapy, individualized tumor vaccines, immune checkpoint blockage therapy, and a host of other tumor immunotherapies provides a promising approach to cancer treatment.…”

“…As transient carriers of genetic information, in vitro transcribed mRNAs, can be produced without genome integration by enabling the production of encoded proteins with great flexibility . The success of the SARS-CoV-2 mRNA vaccine and the COVID-19 mRNA vaccine has driven the rapid development of mRNA technology in tumor therapy SARS-CoV-2 mRNA. , Recently, many stable and effective mRNA packaging nanotechnologies have been developed to protect mRNAs from degradation by RNA enzymes and to efficiently deliver mRNAs into target cells. , Pérez-Núñez et al targeted CSCs in TNBC for low expression of ligand-dependent coinhibitory factor (LCOR), which promotes tumor immune escape, and combined the use of extracellular vesicle-delivered LCOR mRNAs with a PD-L1 inhibitor, which was able to overcome drug resistance in TNBC and eradicate the cancer in preclinical model (Figure D) . The application of mRNA therapy to CAR-T therapy, individualized tumor vaccines, immune checkpoint blockage therapy, and a host of other tumor immunotherapies provides a promising approach to cancer treatment. − Of course, there are still some problems waiting to be addressed: first, how to select appropriate tumor antigens is the core issue of mRNA therapy.…”

DNA mismatch repair in cancer immunotherapy

“…Lipid nanoparticles have been widely used to deliver mRNA for personalized therapy ( 124 ). In a recent study, Liu et al delivered a constitutively active STING mRNA (STING R284S ) to STING-deficient cancer cells using lipid nanoparticles and achieved the production of IFNs and other anti-tumor cytokines to enhance the anti-tumor cell killing activity ( 125 ). Unlike traditional STING agonists, which can induce host T cell cytotoxicity and only work in STING-proficient tumors, STING R284S mRNA delivery with lipid nanoparticles can specifically target on tumor cells without activating the host innate immune response and causing systemic inflammation.…”