Seema Gupta and Bilikere Dwarakanath* Pages 1 - 11 ( 11 )
The tumor microenvironment (TME) comprising of stroma and various components of the immune system forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism manifesting in Warburg phenotype (enhanced aerobic glycolysis) occurs in tumor as well as non-tumor cells. This reprogramming plays a significant role in suppressing the immune attack on the tumor cells leading to cancer cell survival, proliferation and resistance to therapies. Therefore, there is a considerable interest in developing therapeutic strategies involving metabolic modifiers to improve the efficacy of therapy that restores immune competence, besides enhancing cytotoxicity of tumor cells by targeting metabolic reprogramming. Inhibitors of glycolysis like 2-deoxy-D-glucose (2-DG; a hexokinase inhibitor), dichloroacetate and small molecule inhibitors of lactate transport (MCT-1) are some of the metabolic modifiers investigated for their therapeutic as well as adjuvant potential. Among these, 2-DG has been widely investigated and established as an ideal adjuvant in the radio- and chemotherapy of tumors. Selective modulation of the immunobiome of the host-tumor interactions such as cytokine shifts, differential transcriptional regulation, abrogation of immunosuppressive network by 2-DG and reduction in the accumulation of tumor lactate by dichloroacetate are among the contributing factors for immune stimulation linked to the radiosensitization by glycolytic inhibitors.
Glycolysis, metabolic modifiers, 2-DG, immune modulation, radiosensitization, immunosuppression, immunostimulation
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 4 20007, Shanghai Proton and Heavy Ion Center, Shanghai 201321