Spleen-targeted neoantigen mRNA vaccine induces ISG15<sup>+</sup> CD8<sup>+</sup> T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma.
basic_science · Level V
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- Record sourced from PubMed, PMID 42013842.
- Also identified by DOI 10.1016/j.xcrm.2026.102754.
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Abstract
The efficacy of neoantigen vaccine for advanced hepatocellular carcinoma (HCC) is limited largely due to insufficient T cell mobilization and activation. Herein, we develop a spleen-targeted neoantigen mRNA vaccine (STNvac) with highly efficient spleen-selective mRNA transfection. Using a three-dose vaccination regimen, STNvac demonstrates remarkable therapeutic efficacy in orthotopic HCC model with a high likelihood of complete tumor regression and significantly improved survival rates (p < 0.0001). Notably, we identify a distinct ISG15<sup>+</sup> CD8<sup>+</sup> T cell population as crucial mediators of STNvac-induced immunity with potent antigen-processing and cytotoxic capacities. Intriguingly, STNvac promotes the formation of tertiary lymphoid structures (TLSs) through GZMA-F2R-mediated interactions between ISG15<sup>+</sup> CD8<sup>+</sup> T cells and antigen-presenting cells (APCs), which is also confirmed in HCC patients. Taken together, our findings demonstrate the potent antitumor efficacy of spleen-targeted mRNA vaccine and reveal its underlying immune cell interactive mechanisms, presenting high potential for clinical translation.