Tailored HER2 ECD mRNA-LNP vaccines boost CD8+ T cell-mediated antitumor immunity for HER2-positive tumor suppression.

HER2-positive tumors persist as a formidable therapeutic challenge despite advances in targeted agents, chemotherapy, and immunotherapy. Recently, messenger RNA (mRNA) vaccines have emerged as promising avenues for the treatment of advanced tumors and their recurrence, although their clinical application remains challenging. Herein, we developed lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines encoding the modified extracellular domain (ECD) sequence from rat HER2 (rHER2 ECD mRNA-LNP) and human HER2 (hHER2 ECD mRNA-LNP). While both vaccines elicited effective tumor inhibition, the hHER2 ECD mRNA-LNP demonstrated superior prophylactic and therapeutic efficacy in vivo, and successfully induced potent, antigen-restricted cytotoxicity against human patient-derived organoids (PDOs) ex vivo. Mechanistically, it enhances both humoral and T cell responses, and reprograms CD8+ tumor-infiltrating lymphocytes (TILs) by reducing exhaustion, promoting effector maturation, and inducing memory T cells. Specifically, a reduction in naive-like T cell clusters coupled with an elevation in cycling T cell clusters underpins the vaccine's efficacy. Furthermore, HER2 epitope-specific T cell receptor β-chain variable/joining (Trbv/Trbj) combinations and complementarity-determining region 3 (CDR3) motifs were identified as key contributors to the antigen-specific tumoricidal activity. Crucially, combining the hHER2 ECD mRNA-LNP vaccine with programmed cell death-1 (PD-1) immune checkpoint blockade (ICB) achieves superior antitumor efficacy compared to vaccine monotherapy. Moreover, combining the hHER2 ECD mRNA-LNP vaccine with standard chemoradiotherapy effectively potentiates the therapeutic efficacy against HER2-positive tumors. These findings highlight a promising agent for oncology and suggest that modified HER2 ECD mRNA-LNPs represent a viable and highly effective therapeutic strategy against HER2-positive malignancies.