Abstract 854: Targeting Irg1 expressed on macrophages in lymph nodes promotes response to mRNA cancer vaccines

Abstract mRNA cancer vaccines show great promise for tumor therapy, but their therapeutic efficacy is limited. Metabolites play critical roles in immunomodulation, however, their role in mRNA cancer vaccines remains unclear. Using metabolome analysis combined with single-cell RNA sequencing, we found that macrophage-derived itaconate increased markedly after ovalbumin-encoding mRNA-lipid nanoparticle (OVA-LNP) injection in activated ipsilateral lymph nodes compared to that in homeostatic contralateral lymph nodes. Depleting the immune-responsive gene 1(Irg1) in macrophages, which encodes the itaconate-production enzyme aconitate decarboxylase (ACOD1), improved the antigen presentation of dendritic cells and the functions of T cells. Knockdown of Irg1 using small interfering RNA (siRNA) combined with OVA mRNA in LNPs enhanced the therapeutic efficacy of mRNA vaccines alone or combined with an anti-programmed cell death-1 antibody. Taken together, our results reveal a link between itaconate and mRNA cancer vaccines, and suggest that targeting Irg1 via siRNA-LNP may be a promising strategy for improving the therapeutic efficacy of mRNA cancer vaccines. Citation Format: Chao Wan, Wenwen Wei, Xiao Yang, Yeshan Chen, Mengjie Che, You Qin, Qiao Li, Kunyu Yang. Targeting Irg1 expressed on macrophages in lymph nodes promotes response to mRNA cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 854.