2. Academic Validation
  3. Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes

Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes

  • Theranostics. 2025 May 25;15(13):6329-6346. doi: 10.7150/thno.110305.
Wenwen Wei 1 2 3,  Xiao Yang 1 2 3,  Yeshan Chen 1 2 3,  Mengjie Che 1 2 3,  Ying Ye 1 2 3,  Yue Deng 1 2 3,  Mengyao Su 1 2 3,  Yajie Sun 1 2 3,  Jingshu Meng 1 2 3,  Yan Hu 1 2 3,  Jiacheng Wang 1 2 3,  Yijun Wang 1 2 3,  Zishan Feng 1 2 3,  Zhiyuan Zhou 1 2 3,  Yan Li 1 2 3,  Qian Li 1 2 3,  Zhanjie Zhang 1 2 3,  Bian Wu 1 2 3,  Haibo Zhang 4,  You Qin 1 2 3,  Lu Wen 1 2 3,  Chao Wan 1 2 3,  Kunyu Yang 1 2 3
Affiliations

Affiliations

  • 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3 Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China.
  • 4 Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310000, China.
PMID: 40521193 DOI: 10.7150/thno.110305
Abstract

Rationale: mRNA Cancer vaccines show great promise for tumor therapy, but the therapeutic efficacy is limited. Metabolites play critical roles in immunomodulation. However, their role in mRNA Cancer vaccines remains poorly understood. Methods: Metabolome analysis and single-cell RNA sequence were performed to explore the most important metabolite and its source cell. B16-F10-OVA-bearing wide-type and Irg1-depleted C57BL/6 mice were treated with OVA-LNP, OVA&si-Irg1-LNP, or anti-PD-1 antibody to evaluate therapeutic efficacy. Flow cytometry analysis was used to examine the immune cells within the lymph nodes, spleens, and the tumor immune environment. Results: We found that macrophage-derived itaconate was increased markedly in activated ipsilateral lymph nodes after ovalbumin-encoding mRNA-lipid nanoparticle (OVA-LNP) injection, compared to homeostatic contralateral lymph nodes. Depleting the immune-responsive gene 1(Irg1), which encodes the itaconate-production enzyme aconitate decarboxylase (ACOD1), in macrophages improved dendritic cell antigen presentation and enhances T cell function. Combining Irg1 knockdown via small interfering RNA (siRNA) with OVA mRNA in LNPs augmented the therapeutic efficacy of mRNA Cancer vaccines, both as monotherapy and in combination with an anti-programmed cell death-1 antibody. Conclusions: Our findings reveal a link between itaconate and mRNA Cancer vaccines, suggesting that targeting Irg1 via siRNA-LNP could be a promising strategy to improve the therapeutic efficacy of mRNA Cancer vaccines.

Keywords

DCs; anti-PD-1 antibody; mRNA cancer vaccines; macrophages; taconate.

Figures
Products