Taming Tumor Glycolysis and Potential Implications for Immunotherapy

Abstract

Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Besides the coincidence in their historical documentation and concurrent recognition as hallmarks of cancer, both immune evasion and metabolic deregulation may be functionally linked as well. For example, the metabolic phenotype, particularly tumor glycolysis (aerobic glycolysis), impacts the tumor microenvironment (TME), which in turn acts as a major barrier for successful targeting of cancer by antitumor immune cells and other therapeutics. Similarly, in the light of recent research, it has been known that some of the immune sensitive antigens that are downregulated in cancer may also be restored or induced by cellular/metabolic stress. For instance, cancer cells downregulate the cell surface ligands such as MHC class I chain-related (MIC) protein-(A/B) that are normally upregulated in disease/pathological conditions. Noteworthy, the MHC class I chain-related protein A and B (MIC-A/B) are recognized by natural killer (NK) cells for immune elimination. Interestingly, MIC-A/B is stress inducible as demonstrated by oxidative stress and other cellular-stress factors. Consequently, stimulation of metabolic stress has also been shown to sensitize cancer cells to NK cell-mediated cytotoxicity. Taken together, data from recent reports imply that dysregulation of tumor glycolysis could facilitate induction of immune sensitive surface ligands leading to increased efficacy of antitumor immunotherapeutics. Nonetheless, dysregulated tumor glycolysis may also impact the TME and alter it from acidic, low pH into a therapeutically desirable TME that can enhance the effective infiltration of antitumor immune cells. In this mini-review, targeting tumor glycolysis has been discussed to evaluate its potential implications to enhance and/or facilitate anticancer immunity.

Keywords: cancer metabolism; immunotherapy; tumor glycolysis; tumor microenvironment.

Figure 1

A schematic showing major immune-evasive mechanisms that enable cancer cells to escape immune surveillance and antitumor immunity.

Figure 2

Potential anticancer immunotherapeutic opportunities of dysregulation of tumor glycolysis. (A) A schematic showing that dysregulation of tumor glycolysis alters tumor microenvironment that in turn could facilitate effective infiltration of antitumor immune cells. (B) Diagrammatic representation of dysregulation of tumor glycolysis to upregulate the stress-inducible surface ligands for further sensitization to natural killer (NK) cell-mediated cytotoxicity. (C) A schematic showing potential outcomes of induction of metabolic stress by dysregulation of tumor glycolysis.