Methods of treating cancer or reducing the incidence of relapse of a cancer in a subject comprising co-administration of Toll-like receptor (TLR) 4 ligand, such as an HMGN1 protein, and a TLR 7 or 8 ligand, and optionally an immune checkpoint inhibitor, to the subject in need of such therapy. The TLR4-mediated immune-stimulating effect is synergistically enhanced by ligands of TLR7 or 8, and the immune checkpoint inhibitor. Also described here is a nanoparticle delivery platform for the co-administration of the TLR 4 ligand and the TLR 7 or 8 ligand.