Designing a tumor landscape-modifying vaccine with a unique TLR2/6 agonist for refractory pancreatic cancer

Failure of cancer vaccines in clinical trials has been linked to poor preclinical translatability, immunosuppressive tumor microenvironments (TMEs), suboptimal antigen delivery to antigen-presenting cells, limited human MHC antigenicity, and insufficiently safe immune adjuvants. Therefore, this study aimed to design an integrated cancer vaccine and evaluate its efficacy in a KPC orthotopic pancreatic cancer model containing the G12D mutation. A novel immune adjuvant, C-VAX, was developed from the natural Toll-like receptor 2/6 agonist UNE-C1 and covalently linked to a KRAS G12D neoantigen and WNT5a, a tumor-associated antigen upregulated in resistant tumors. This integrated vaccine enhanced CD8⁺ T-cell infiltration and reduced α-SMA expression in the TME. The therapeutic effects were further enhanced following anti–PD-1 checkpoint blockade. These findings suggest that vaccines targeting tumor antigens and resistance-associated TME components may promote an immune-responsive TME in refractory cancers.