Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy

Abstract

Hypoxia is not only a prominent contributor to the heterogeneity of solid tumors but also a crucial stressor in the microenvironment to drive adaptations for tumors to evade immunosurveillance. Herein, we discuss the potential role of hypoxia within the microenvironment contributing to immune resistance and immune suppression of tumor cells. We outline recent discoveries of hypoxia-driven adaptive mechanisms that diminish immune cell response via skewing the expression of important immune checkpoint molecules (e.g., cluster of differentiation 47, programmed death ligand 1, and human leukocyte antigen G), altered metabolism and metabolites, and pH regulation. Importantly, inhibition of hypoxic stress-relevant pathways can collectively enhance T-cell-mediated tumor cell killing. Furthermore, we discuss how manipulation of hypoxia stress may pose a promising new strategy for a combinational therapeutic intervention to enhance immunotherapy of solid tumors.

Keywords: hypoxia; immunosuppression; immunotherapy; metabolism; microenvironment.

Figure 1

Regulation of HIF-1α levels and downstream genes under normoxic and hypoxic conditions. Under normoxic conditions, HIF-1α is hydroxylated and further undergoes degradation through an ubiquitination-dependent process mediated by VHL. Under hypoxic conditions, HIF-1α is stabilized and forms a complex with HIF-1β, which induces transcriptions of various genes involved in angiogenesis, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and immune regulation.

Figure 2

Schematic representation of two major pathways of hypoxia-driven extracellular acidity by tumor cells. (1) Under hypoxic conditions, glucose goes through glycolysis and produces pyruvate, which is mainly converted to lactic acid by lactate dehydrogenase A (LDHA). Lactic acid is exported by MCT4 resulting in acidification of the tumor microenvironment. (2) Under hypoxic conditions, glutamine goes through tricarboxylic acid (TCA) cycle and releases CO₂, which can be converted into HCO₃⁻ and H⁺. HCO₃⁻ is transported back to tumor cells by bicarbonate transporters (BT), and accumulation of extracellular H⁺ leads to tumor acidosis.

Figure 3

Schematic representation of hypoxia upregulating immunosuppressive adenosine signaling pathway in cancer cells. Under hypoxic conditions, the upregulation of CD39 and CD79 expressions lead to increase of adenosine, which has been shown to have immunosuppressive effects on Teff, DC, and NK cells.