A recent study published in ACS Nano explored a novel strategy to reprogram the liver’s immune environment and generate an antitumor response against metastatic pancreatic cancer.
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Researchers developed lipid nanoparticles (LNPs) that deliver both messenger RNA (mRNA) encoding the KRAS G12D neoantigen and cyclic GMP-AMP (cGAMP), a stimulator of the interferon genes (STING) pathway.
This dual approach aims to activate type I interferon signaling, promoting cytotoxic T cell responses and enhancing immune recognition of pancreatic tumors.
Challenges in Pancreatic Cancer Treatment
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with a five-year survival rate of just 12 %. It spreads rapidly, often forming metastases in the liver. The liver naturally suppresses immune responses, allowing cancer cells to evade detection. Overcoming this immune suppression is key to improving treatment.
Existing immunotherapies struggle to generate strong and lasting immune responses against PDAC. This study tested whether LNPs carrying KRAS G12D mRNA and cGAMP could shift the liver’s immune environment from suppression to activation, improving the body’s ability to recognize and attack metastatic tumors.
LNP Synthesis and Experimental Approach
Researchers synthesized the LNPs using a microfluidics technique, encapsulating KRAS G12D mRNA and cGAMP within ionizable lipid MC3 nanoparticles. The resulting particles were approximately 90 nm in diameter. After intravenous injection, the LNPs successfully reached liver nonparenchymal cells. In vitro assays confirmed that the nanoparticles activated the type I interferon pathway in antigen-presenting cells (APCs).
To assess their therapeutic effect, the study used a mouse model with metastatic PDAC expressing KRAS G12D. Immune activation was measured using enzyme-linked immunospot (ELISPOT) assays, which quantified interferon-gamma (IFN-γ) producing T cells. The study tested both preventive and therapeutic treatments, comparing immune responses and survival rates between treated and control groups.
Key Findings
Intravenous administration of the cGAMP/mKRAS/LNPs significantly activated the type I interferon pathway, leading to the generation of CD8+ cytotoxic T cells capable of recognizing and attacking metastatic cancer cells. This immune activation was confirmed by the increased expression of CD80 and CD86 on liver APCs, which play a key role in T cell activation and proliferation.
Adoptive transfer experiments showed that the immune response was not only effective in generating immediate cytotoxicity against liver metastases but also capable of producing memory T cells, providing long-term immune protection in naïve recipient mice. Additionally, the delivered mRNA recruited immune effector cells to the tumor site, leading to substantial tumor regression and prolonged survival in treated animals compared to controls.
The findings suggest that combining KRAS mRNA with a STING agonist strengthens the immune response against PDAC. Using mRNA to introduce neoantigens while simultaneously activating the immune system with cGAMP offers a more effective approach than traditional immunotherapies, which often struggle to generate strong responses in solid tumors. The improved survival outcomes highlight the potential of this dual-delivery system in limiting metastatic growth and enhancing overall prognosis in pancreatic cancer.
Implications and Future Research
This study demonstrates a method for shifting the liver’s immune environment from suppression to activation using LNPs. Delivering both KRAS mRNA and cGAMP provided both preventive and therapeutic benefits, suggesting potential applications in other cancers with immunosuppressive environments.
Future research should focus on optimizing the LNP formulation, testing safety and immune response in human trials, and evaluating combination treatments with existing therapies. Further studies could explore how this approach applies to other tumor types.
Journal Reference
Xu, X., et al. (2025). Reprogramming the tolerogenic immune response against pancreatic cancer metastases by lipid nanoparticles delivering a STING agonist plus mutant KRAS mRNA. ACS Nano. DOI: 10.1021/acsnano.4c14102, https://pubs.acs.org/doi/10.1021/acsnano.4c14102