Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration

Abstract

Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytically activated immune cells often become anergic, leading to an increase in immune checkpoint proteins such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Therefore, using a nanoparticle-delivered agent to preferentially inhibit glycolysis in tumor cells, and not in immune cells, has the potential to attenuate the expression of checkpoint proteins. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) containing a prodrug of dichloroacetate (DCA), a PDK1 inhibitor. We demonstrated that the targeted NP alters the TME which results in increased immunological activation against cancer cells, causing a decrease in mean tumor volume. Here, we also show findings that when Mito-DCA, a prodrug of DCA, was combined with anti-PD-1, a checkpoint inhibitor, results from in vivo syngeneic models showed an upregulation in the number of tumor infiltrating lymphocytes. This work provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells.