Gasotransmitters bridging tumor biology and immunity: from pathophysiological insights to therapeutic potential – Research

Figure 1

Figure 1

Immune-mediated signaling networks promoting gasotransmitters production in the TME. Gasotransmitters production is regulated by multiple signaling networks activated by different cell populations within the TME. As graphically represented in the figure, immune cells (including macrophages, dendritic cells, MDSCs and T cells), along with endothelial cells, fibroblasts and tumor cells release soluble factors that orchestrate several signaling cascades (i.e. HIF-1α/2α, NF-kB, NRF2, AP-1 and STAT3). These pathways drive the transcription of specific enzymes (HO-1; CSE, CBS, 3-MST, CARS2 and NOS) in immune, stromal and tumor cells ultimately resulting in gasotransmitters production (CO, H₂S and NO. Depending on their concentrations and spatial localization within the TME, these intracellular mediators can exert either anti-inflammatory or pro-inflammatory effects, leading to context-dependent (yellow boxes) outcomes that may be either beneficial (anti-cancer effects-green boxes) or detrimental (pro-cancer effects- red boxes). (MDSC, Myeloid-Derived Suppressor Cells; HIF-1α/2α, Hypoxia-Inducible Factor 1-alpha/2-alpha; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NRF2, Nuclear Factor Erythroid 2–Related Factor 2; AP-1, Activator Protein 1; STAT3, Signal Transducer and Activator of Transcription 3; HO-1, Heme Oxygenase-1; CO, Carbon Monoxide; sGC, Soluble Guanylate Cyclase; cGMP, Cyclic Guanosine Monophosphate; MAPK, Mitogen-Activated Protein Kinase; VEGF, Vascular Endothelial Growth Factor; TGF-β, Transforming Growth Factor β; NOTCH-1, Notch receptor 1; KATP, ATP-sensitive potassium channel; ERK1/2, Extracellular Signal-Regulated Kinase 1/2; JNK, c-Jun N-terminal Kinase; PI3K/AKT, Phosphoinositide 3-Kinase/Protein Kinase B; HCY, Homocysteine; Cys, Cysteine; CAT, Cysteine Aminotransferases; CSE, Cystathionine Gamma-Lyase; CBS, Cystathionine Beta-Synthase; 3-MT, 3-Mercaptopyruvate; 3-MST, 3-Mercaptopyruvate Sulfurtransferase; IRS, Insulin Receptor Substrate; CARS2, Cysteinyl-tRNA Synthetase 2; H₂S, Hydrogen Sulfide; SRBs, Sulfate Reducing Bacyteria; cAMP, cycline Adenosine Monophosphate; PKA, Protein Kinase A; MMPs, Metalloproteinases; VEGFR2, Vascular Endothelial Growth Factor Receptor 2; L-arg, L-Arginine; BH₄, Tetrahydrobiopterin; FMN, Flavin Mononucleotide; FAD, Flavin Adenine Dinucleotide; CaM, Calmodulin; NOS, Nitric Oxide Synthase; O₂, Oxygen; NADPH, Nicotinamide Adenine Dinucleotide Phosphate; NO, Nitric Oxide; L-cit, L-Citrulline; PEBP-1, Phosphatidylethanolamine-Binding Protein 1; PCNA, Proliferating Cell Nuclear Antigen; PKG, Protein Kinase G; PKC, Protein Kinase C) Created by