Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Suppressive Barriers to Eliminate Pancreatic Cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy carrying a five-year survival of about 10%. The immunosuppressive milieu in PDAC tumors has proven a significant hurdle to new and existing treatments, resulting in survival statistics that have barely changed in the last 5 decades. Here we present a novel combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to the tumor of murine models of PDAC. This treatment was effective against primary and metastatic models of PDAC, leading to a dramatic reduction in tumor growth and even achieving cures in both settings. IL-12 protein concentrations were transient and remained localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming these cells were the key players in the anti-tumor immune response generated. Subsequent single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT was responsible for eliciting T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function, which was shown to be dependent on IFN.This is the first report of its kind demonstrating the utility of SBRT and IL-12 mRNA in PDAC.

ORGANISM(S): Mus musculus

PROVIDER: GSE242111 | GEO | 2026/08/29

REPOSITORIES: GEO