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

ABSTRACT 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.