Nanoparticle-mediated delivery of 2-deoxy-D-glucose induces antitumor immunity and cytotoxicity in liver tumors in mice

Abstract Background & Aims Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect is recently gathering attention as a cancer immune resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against HCC in mice. Methods The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models. Results The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T cell trafficking. Additionally, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ-positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP-treated Huh7 cells revealed their increased interferon-γ production and glucose uptake compared to the CD8+ T cells cocultured with PLGA-NP-treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8+ T cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/10) production in liver tumors via interferon-γ-Janus kinase-signal transducers and activator of transcription pathway and AMP-activated protein kinase-mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti-programmed death-1 (anti-PD1) antibody but also suppressed anti-PD1-resistant tumors. Conclusions The newly developed 2DG-PLGA-NPs demonstrated antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.