Spleen-targeted neoantigen mRNA vaccine induces ISG15⁺ CD8⁺ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma

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 + CD8 + 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 + CD8 + 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.

Abstract of "Spleen-targeted neoantigen mRNA vaccine induces ISG15⁺ CD8⁺ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma" by Lin X, Chen G, Tang R et al., https://doi.org/10.1016/j.xcrm.2026.102754, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.