Therapeutic tumor neoantigen vaccines have been widely studied given their good safety profile and ability to avoid central thymic tolerance. However, targeting antigen-presenting cells (APCs) and inducing robust neoantigen-specific cellular immunity remain challenges. Here, a safe and broad-spectrum neoantigen vaccine delivery system is proposed (GP-Neoantigen) based on β-1,3-glucan particles (GPs) derived from Saccharomyces cerevisiae and coupling peptide antigens with GPs through convenient click chemistry. The prepared system has a highly uniform particle size and high APC targeting specificity. In mice, the vaccine system induced a robust specific CD8 T cell immune response and humoral immune response against various conjugated peptide antigens and showed strong tumor growth inhibitory activity in EG7·OVA lymphoma, B16F10 melanoma, 4T1 breast cancer, and CT26 colon cancer models. The combination of the toll-like receptors (TLRs) agonist PolyI:C and CpG 2395 further enhanced the antitumor response of the particle system, achieving complete tumor clearance in multiple mouse models and inducing long-term rejection of reinoculated tumors. These results provide the broad possibility for its further clinical promotion and personalized vaccine treatment.