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Abstarct Background Cytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy. However, unmodified CpG are not very efficient in clinical trials. Glucose, ligand of C-type lectin receptors (CLRs), can promote DC maturation and antigen presentation, which is the first step of induction of adaptive immune responses. Therefore, conjugation of type B CpG DNA to glucose-containing glycopolymers may enhance the therapeutic effects against tumor by CpG-based vaccine. Methods gCpG was developed by chemical conjugation of type B CpG DNA to glucose-containing glycopolymers. The therapeutic effects of gCpG-based vaccine were tested in both murine primary melanoma model and its metastasis model. Results gCpG based tumor vaccine inhibited both primary and metastasis of melanoma in mice which was dependent on CD8 + T cells and IFNγ. In tumor microenvironment, gCpG treatment increased Th1 and CTL infiltration, increased M1 macrophages, decreased Tregs and MDSCs populations, and promoted inflammatory milieu with enhanced secretion of IFNγ and TNFα. The anti-tumor efficacy of gCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. Conclusions We confirmed that gCpG was a promising adjuvant for vaccine formulation by activating both tumor-specific Th1 and Tc1 responses, and regulating tumor microenvironments. Graphical Abstract

Inducing tumor-specific T cell responses and regulating suppressive tumor microenvironments have been a challenge for effective tumor therapy. CpG (ODN), the Toll-like receptor 9 agonist, has been widely used as adjuvants of cancer vaccines to induce T cell responses. However, clinical benefits of CpG based tumor vaccine were limited primarily due to the poor targeting to lymph nodes. Here we developed a lipid-glycoadjuvant@AuNPs (LCpG) by covalent conjugation of CpG with lipid-glycopolymers, which could be rapidly transported to and retained longer in the lymphoid nodes than unmodified CpG. In melanoma model, LCpG controlled both primary tumor and its metastasis, and established long-term memory. In spleen and tumor draining lymphoid nodes, LCpG activated tumor-specific Tc1 responses, with increased CD8+ T-cell proliferation, antigen–specific Tc1 cytokine production and specific-tumor killing capacity. In tumor microenvironments, antigen-specific Tc1 induced by the LCpG promoted CTL infiltration, skewed tumor associated macrophages to M1 phenotype, inhibited Treg differentiation and induced proinflammatory cytokines production in a CTL-derived IFN-γ-dependent manner. In vivo cell depletion and adoptive transfer experiments confirmed that antitumor activity of LCpG included vaccine was mainly dependent on CTL-derived IFN-γ. The anti-tumor efficacy of LCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. Together, our results demonstrated that LCpG was a promising adjuvant for vaccine formulation which could augment tumor-specific Tc1 activity, and regulate tumor microenvironments.