Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

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It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly contributes to the harsh tumor microenvironment (TME) and ultimately impairs immune cell fitness and effector functions. The major aims of this review are to provide an overview on the immune system in cancer; to position oxygen shortage and metabolic competition as the ground of a restrictive TME and as important players in the anti-tumor immune response; to define how immunotherapies affect hypoxia/oxygen delivery and the metabolic landscape of the tumor; and vice versa, how oxygen and metabolites within the TME impinge on the success of immunotherapies. By analyzing preclinical and clinical endeavors, we will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs.

Graphical AbstractHighlights d Vitamin B3 analogs improve hematopoietic stem cell (HSC) and progenitor function d Nicotinamide riboside (NR) increases mitochondrial recycling in HSCs d In vitro NR exposure induces asymmetric mitochondrial distribution in dividing HSCs d NR dietary supplementation improves survival after HSC transplantation in mice SUMMARYIt has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD + -boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD +boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo-and radiotherapy.

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The scientific knowledge about tumor metabolism has grown at a fascinating rate in recent decades. We now know that tumors are highly active both in their metabolism of available nutrients and in the secretion of metabolic by-products. However, cancer cells can modulate metabolic pathways and thus adapt to specific nutrients. Unlike tumor cells, immune cells are not subject to a ‘micro-evolution’ that would allow them to adapt to progressing tumors that continuously develop new mechanisms of immune escape. Consequently, immune cells are often irreversibly affected and may allow or even support cancer progression. The mechanisms of how tumors change immune cell function are not sufficiently explored. It is, however, clear that commonly shared features of tumor metabolism, such as local nutrient depletion or production of metabolic ‘waste’ can broadly affect immune cells and contribute to immune evasion. Moreover, immune cells utilize different metabolic programs based on their subtype and function, and these immunometabolic pathways can be modified in the tumor microenvironment. In this review and accompanying poster, we identify and describe the common mechanisms by which tumors metabolically affect the tumor-infiltrating cells of native and adaptive immunity, and discuss how these mechanisms may lead to novel therapeutic opportunities.

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