The emerging "hallmarks" of metabolic reprogramming and immune evasion: distinct or linked?

The role of the immune system in tumor elimination has been shown to be increasingly ambiguous, as many tumors not only escape recognition by the adaptive immune response but also even prime the immune cells to promote tumor growth. This effect is achieved through a number of mechanisms, which include both direct interference with the cells of the adaptive immune response and indirect immunosuppression achieved through modification of the tumor microenvironment. We propose that through upregulation of glycolysis and the consequent lowering of pH in the tumor microenvironment, tumors can take advantage of a pH control system, already exploited by specific immune cell subpopulations, to gain control of the immune system and suppress both cytotoxic and antigen-presenting cells. This is accomplished through the direct competition of tumor cells with actively proliferating glycolytic immune cells for glucose and indirectly through the creation by the tumor of a microenvironment that interferes with maturation and activation of antigen-presenting cells and naïve cytotoxic T cells. Immunosuppressive properties of an acidic microenvironment in the vicinity of the tumor can thus provide additional benefits for upregulation of glycolysis by tumor cells, suggesting that the two emerging "hallmarks of cancer," altered glucose metabolism and immune suppression, are in fact fundamentally linked.