A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment.

Abstract

The promising results of immunotherapy in tumors have changed the current treatment modality for cancer. However, the remarkable responses are limited to a minority of patients, which is due to immune suppression in the tumor microenvironment (TME). These include the pre-exists of suppressive immune cells, physical barriers to immune infiltration, antigen and antigen presentation deficiency, and expression of inhibitory immune checkpoint molecules. Recently, increasing evidence reveal that tumor metabolism, especially abnormal glucose metabolism of tumors, plays an essential role in tumor immune escape and is a potential target to combine with immunotherapy. By glucose uptake, tumor cells alter their metabolism to facilitate unregulated cellular proliferation and survival and regulate the expression of inhibitory immune checkpoint molecules. Meanwhile, glucose metabolism also regulates the activation, differentiation, and functions of immunocytes. In addition, tumor mainly utilizes glycolysis for energy generation and cellular proliferation, which cause the TME to deplete nutrients for infiltrating immune cells such as T cells and produce immunosuppressive metabolites. Thus, therapeutics that target glucose metabolism, such as inhibiting glycolytic activity, alleviating hypoxia, and targeting lactate, have shown promise as combination therapies for different types of cancer. In this review, we summarized the functions of glucose metabolism in the tumor cells, immune cells, and tumor microenvironment, as well as strategies to target glucose metabolism in combination with immune checkpoint blockade for tumor therapy.