Self-Assembling Peptide-Adjuvant Conjugate (SaPAC) Platform for Precision Cancer Immunotherapy

Peptide cancer vaccines often suffer from poor lymphatic drainage, limited antigen-presenting cell uptake, and weak innate immune activation. To overcome these barriers, we engineered the Self-Assembling Peptide-Adjuvant Conjugate (SaPAC) platform, which covalently links neoantigen epitopes to the TLR7 agonist 1V209 through site-selective lysine conjugation. Synthesized by Fmoc solid-phase peptide synthesis, SaPAC conjugates self-assemble into cationic nanoparticles with hydrodynamic diameters of approximately 100-200 nm. Compared with unconjugated self-assembling peptide nanoparticles mixed with soluble adjuvant, SaPAC nanoparticles enhanced lymphatic drainage and antigen persistence in draining lymph nodes. Mechanistically, SaPAC activated the TLR7-MyD88 axis, promoted plasmacytoid dendritic cell and macrophage recruitment, drove APC maturation (CD80⁺CD86⁺), and enhanced MHC-I cross-presentation to amplify antigen-specific CD8+ T-cell priming. Therapeutically, SaPAC monotherapy suppressed tumor growth in B16-OVA melanoma and MB49 bladder carcinoma models by increasing intratumoral infiltration of activated CD8+ T cells and NK cells. In an orthotopic 4T1 triple-negative breast cancer model, multivalent SaPAC vaccination synergized with anti-PD-1 blockade and achieved durable tumor suppression comparable to the Poly(I:C)-adjuvanted benchmark without detectable systemic toxicity. Collectively, SaPAC represents a chemically defined platform that bridges innate and adaptive anti-tumor immunity.