Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment

Abstract

The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.

Keywords: biochemistry; cancer; immunometabolism.

Figure 1

Nitric oxide concentration-dependent signaling and functional effects.

Figure 2

Sites for NO activity along glycolysis, the PPP, and the TCA. Green boxes/(II) represent intermediate levels of NO (nitrosative signaling) and red boxes/(III) indicate high levels of NO (nitrosative stress) required for NO interaction at the indicated site. Red arrows indicate inhibitory mechanisms while blue arrows indicate activating mechanisms.

Figure 3

Sites for NO interaction with the a-KG node, as well as its associated amino acid paths. Green boxes/(II) represent intermediate levels of NO (nitrosative signaling) and red boxes/(III) indicate high levels of NO (nitrosative stress) required for NO interaction at the indicated site. Red arrows indicated inhibitory mechanisms while blue arrows indicate activating mechanisms.

Figure 4

Sites along arginine and sulfur metabolic paths for NO interaction. Green boxes/(II) represent intermediate levels of NO (nitrosative signaling) and red boxes/(III) indicate high levels of NO (nitrosative stress) required for NO interaction at the indicated site. Red arrows indicated inhibitory mechanisms while blue arrows indicate activating mechanisms.

Figure 5

Downstream signaling pathways affected by NOS2/NO activity. Red arrows indicate inhibition while blue arrows indicated activation.

Figure 6

NO reactivity leading to regulation of tryptophan related metabolic pathways. Green boxes/(II) represent intermediate levels of NO (nitrosative signaling) and red boxes/(III) indicate high levels of NO (nitrosative stress) required for NO interaction at the indicated site. Red arrows indicate inhibition, green arrows indicate activation, and broken arrows designate major pathways.