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Reports on the kinetics of the autoxidation of aqueous nitric oxide are discussed. It is concluded that the correct rate law is -d[NO]/dt = 4kaq[NO]2[O2] with kaq = 2 x 10(6) M-2.s-1 at 25 degrees c and that a recent report of a rate law zero order in NO is incorrect.

The reaction kinetics of nitric oxide autoxidation in aerobic solutions were investigated by direct observation of the nitrite ion product and by trapping the strongly oxidizing and nitrosating intermediates formed in this reaction. The rate behavior observed for nitrite formation [rate = k3[O2][NO]2, k3 = (6 +/- 1.5) x 10(6) M-2 s-1 at 22 degrees C] was the same as found for oxidation of Fe(CN)6(4-) and of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and as for the nitrosation of sulfanilamide. There was a slight decrease in k3 to (3.5 +/- 0.7) x 10(6) M-2 s-1 at 37 degrees C. The second-order dependency for NO was observed at NO concentrations as low as 3 microM. The results of the competitive kinetics studies suggest that the key oxidizing intermediates, species which are both strong oxidants and nitrosating agents, are not one of those commonly proposed (NO2, N2O3, NO+, or O2NO-) but are one or more as yet uncharacterized NOx species.

Nitric oxide synthase 2 (NOS2) and its gene product, inducible NOS (iNOS) play an important role in neuroinflammation by generating nitric oxide (NO), a critical signaling and redox factor in the brain. Although NO is associated with tissue damage, it can also promote cell survival. We hypothesize that during long-term exposure to amyloid-beta (Abeta) in Alzheimer's disease (AD), NO levels fall in the brain to a threshold at which the protective effects of NO cannot be sustained, promoting Abeta mediated damage. Two new mouse models of AD have been developed that utilize this concept of NO's action. These mice express human amyloid-beta protein precursor (AbetaPP) mutations that generate Abeta peptides on a mouse NOS2 knockout background. The APP/NOS2(-/-) bigenic mice progress from Abeta production and amyloid deposition to hyperphosphorylated normal mouse tau at AD-associated epitopes, aggregation and redistribution of tau to somatodendritic regions of neurons and significant neuronal loss including loss of interneurons. This AD-like pathology is accompanied by robust behavioral changes. As APP/NOS2(-/-) bigenic mice more fully model the human AD disease pathology, they may serve as a tool to better understand disease progression in AD and the role of NO in altering chronic neurological disease processes. [ABSTRACT FROM AUTHOR]

The roles of nitric oxide (NO) in numerous disease states have generated considerable discussion over the past several years. NO has been labeled as the causative agent in different pathophysiological mechanisms, yet appears to protect against various chemical species such as those generated under oxidative stress. Similarly, NO appears to exert a dichotomy of effects within the multistage model of cancer. Chronic inflammation can lead to the production of chemical intermediates, among them NO, which in turn can mediate damage to DNA. Yet, NO also appears to be critical for the tumoricidal activity of the immune system. Furthermore, NO can also have a multitude of effects on other aspects of tumor biology, including angiogenesis and metastasis. This report will discuss how the chemistry of NO may impact the initiation and progression stages of cancer. [ABSTRACT FROM PUBLISHER]

Abstract Background Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur. Methods We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-Aβ antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with Aβ vaccination for 4 months. Results There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-Aβ immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.

Abstract Background Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Methods Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. Results COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Conclusions Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.

Significance: This work identifies CD8-NOS2+COX2+ and CD8-NOS2-COX2+ unique cellular neighborhoods that drive the tumor immune spatial architecture of CD8+ T cells predictive of clinical outcome and can be targeted with clinically available NOS inhibitors and NSAIDs., (©2024 The Authors; Published by the American Association for Cancer Research.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown modulatory mechanisms responsible for the lack of TRAIL activity in patients. Here, we hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. To test this, we performed an RNAseq analysis of MDA-MB-231 cells treated with TRAIL, followed by validation in additional TNBC cell lines. TRAIL significantly induces expression of multiple cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, the induction of these cytokines was predominantly mediated by death receptor 5, caspase 8 (but not caspase 8 enzymatic activity), and the non-canonical NFKB2 pathway. The cytokines produced by the TRAIL-treated TNBC cells enhanced chemotaxis of healthy human donor isolated neutrophils. In vivo , TRAIL treated TNBC murine xenograft tumors showed activation of the NFKB2 pathway, elevated production of CXCLs and IL-6, and increased neutrophil recruitment into the tumors. Moreover, donor isolated neutrophils preincubated in supernatants from TRAIL-treated TNBC cells exhibited impaired cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies with these neutrophils confirmed their suppressive effect on T cell proliferation and an increase in Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and immune suppression.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER - ) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.

M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys 477 and Cys 484 , and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring., (© 2023. Springer Nature Limited.)

Utilizing targeted therapies capable of reducing cancer metastasis, targeting chemoresistant and self-renewing cancer stem cells, and augmenting the efficacy of systemic chemo/radiotherapies is vital to minimize cancer-associated mortality. Targeting nitric oxide synthase (NOS), a protein within the tumor microenvironment, has gained interest as a promising therapeutic strategy to reduce metastatic capacity and augment the efficacy of chemo/radiotherapies in various solid malignancies. Our review highlights the influence of nitric oxide (NO) in tumor progression and cancer metastasis, as well as promising preclinical studies that evaluated NOS inhibitors as anticancer therapies. Lastly, we highlight the prospects and outstanding challenges of using NOS inhibitors in the clinical setting., (©2022 The Authors; Published by the American Association for Cancer Research.)

A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER breast cancer has been established. However, the mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single-cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNγ combined with IL1β or TNFα. Given that IFNγ is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNγ presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8 + T cells were spatially analyzed in aggressive ER-, TNBC, and HER2 + breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma-restricted CD8 + T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8 + T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis, suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNγ + IL1β/TNFα increased the elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight into distinct neighborhoods where stroma-restricted CD8 + T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Nitrosyl ruthenium complexes are promising platforms for nitric oxide (NO) and nitroxyl (HNO) release, which exert their therapeutic application. In this context, we developed two polypyridinic compounds with the general formula cis -[Ru(NO)(bpy) 2 (L)] n + , where L is an imidazole derivative. These species were characterized by spectroscopic and electrochemical techniques, including XANES/EXAFS experiments, and further supported by DFT calculations. Interestingly, assays using selective probes evidenced that both complexes can release HNO on reaction with thiols. This finding was biologically validated by HIF-1α detection. The latter protein is related to angiogenesis and inflammation processes under hypoxic conditions, which is selectively destabilized by nitroxyl. These metal complexes also presented vasodilating properties using isolated rat aorta rings and demonstrated antioxidant properties in free radical scavenging experiments. Based on these results, the new nitrosyl ruthenium compounds showed promising characteristics as potential therapeutic agents for the treatment of cardiovascular conditions such as atherosclerosis, deserving further investigation.

Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a product of IL27 receptor signaling, in bowel tissue. To determine whether IL-27 acted directly on colonic epithelium, murine colonoids and primary intact colonic crypts were shown to be unresponsive to IL-27 in vitro and to lack detectable IL-27 receptors. On the other hand, macrophages, which are present in inflamed colon tissue, were responsive to IL-27 in vitro . IL-27 induced pSTAT1 in macrophages, the transcriptome indicated an IFN-like signature, and supernatants induced pSTAT1 in colonoids. IL-27 induced anti-viral activity in macrophages and MHC Class II induction. We conclude that the effects of mucosal delivery of IL-27 in murine IBD are in part based on the known effects of IL27 inducing immunosuppression of T cells mediated by IL-10. We also conclude that IL-27 has potent effects on macrophages in inflamed colon tissue, generating mediators that in turn act on colonic epithelium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Andrews, McLean, Hixon, Pontejo, Starr, Malo, Cam, Ridnour, Hickman, Steele-Mortimer, Wink, Young, McVicar, Li and Durum.)

The small endogenous signaling molecule nitric oxide (NO) has been linked with chronic inflammation and cancer. The effects of NO are both concentration and temporally dependent; under some conditions, NO protects against damage caused by reactive oxygen species and activates P53 signaling. During chronic inflammation, NO causes DNA damage and inhibits repair proteins. To extend our understanding of the roles of NO during carcinogenesis, we investigated the possible effects of chronic NO exposure on MCF10A breast epithelial cells, as defined by changes in cellular morphology, chromosome/genomic stability, RNA, and protein expression, and altered cell phenotypes. Human MCF10A cells were maintained in varying doses of the NO donor DETANO for three weeks. Distinct patterns of genomic modifications in TP53 and KRAS target genes were detected in NO-treated cells when compared to background mutations. In addition, quantitative real-time PCR demonstrated an increase in the expression of cancer stem cell (CSC) marker CD44 after prolonged exposure to 300 μM DETANO. While similar changes in cell morphology were found in cells exposed to 300-500 μM DETANO, cells cultured in 100 μM DETANO exhibited enhanced motility. In addition, 100 μM NO-treated cells proliferated in serum-free media and selected clonal populations and pooled cells formed colonies in soft agar that were clustered and disorganized. These findings show that chronic exposure to NO generates altered breast epithelial cell phenotypes with malignant characteristics.

Nitric oxide (NO) and the enzyme that synthesizes it, nitric oxide synthase 2 (NOS2), have emerged as key players in inflammation and cancer. Expression of NOS2 in tumors has been correlated both with positive outcomes and with poor prognoses. The chemistry of NO is the major determinate to the biological outcome and the concentration of NO, which can range over five orders of magnitude, is critical in determining which pathways are activated. It is the activation of specific oncogenic and immunological mechanisms that shape the outcome. The kinetics of specific reactions determine the mechanisms of action. In this review, the relevant reactions of NO and related species are discussed with respect to these oncogenic and immunological signals.

Antitumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8 + T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2 and COX2 tumor expression. Here, we show that NOS2/COX2 levels influence both the polarization and spatial location of lymphoid cells including CD8 + T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8 + T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8 + T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2 - mice. This regimen led to complete tumor regression in ∼20-25% of tumor-bearing Nos2 - mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4 + and CD8 + T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8 + T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAID's may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer., Competing Interests: Declaration of competing interest The authors have no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Donors of nitroxyl (HNO), the one electron-reduction product of nitric oxide (NO . ), positively modulate cardiac contractility/relaxation while limiting ischemia-reperfusion (I/R) injury. The mechanisms underpinning HNO anti-ischemic effects remain poorly understood. Using isolated perfused rat hearts subjected to 30 min global ischemia/1 or 2 h reperfusion, here we tested whether, in analogy to NO . , HNO protection requires PKCε translocation to mitochondria and K ATP channels activation. To this end, we compared the benefits afforded by ischemic preconditioning (IPC; 3 cycles of I/R) with those eventually granted by the NO . donor, diethylamine/NO, DEA/NO, and two chemically unrelated HNO donors: Angeli's salt (AS, a prototypic donor) and isopropylamine/NO (IPA/NO, a new HNO releaser). All donors were given for 19 min before I/R injury. In control I/R hearts (1 h reperfusion), infarct size (IS) measured via tetrazolium salt staining was 66 ± 5.5% of the area at risk. Both AS and IPA/NO were as effective as IPC in reducing IS [30.7 ± 2.2 (AS), 31 ± 2.9 (IPA/NO), and 31 ± 0.8 (IPC), respectively)], whereas DEA/NO was significantly less so (36.2 ± 2.6%, p < 0.001 vs. AS, IPA/NO, or IPC). IPA/NO protection was still present after 120 min of reperfusion, and the co-infusion with the PKCε inhibitor (PKCV1-2500 nM) prevented it (IS = 30 ± 0.5 vs. 61 ± 1.8% with IPA/NO alone, p < 0.01). Irrespective of the donor, HNO anti-ischemic effects were insensitive to the K ATP channel inhibitor, 5-OH decanoate (5HD, 100 μM), that, in contrast, abrogated DEA/NO protection. Finally, both HNO donors markedly enhanced the mitochondrial permeability transition pore (mPTP) ROS threshold over control levels (≅35-40%), an action again insensitive to 5HD. Our study shows that HNO donors inhibit mPTP opening, thus limiting myocyte loss at reperfusion, a beneficial effect that requires PKCε translocation to the mitochondria but not mitochondrial K + channels activation.

The mechanistic roles of nitric oxide (NO) during cancer progression have been important considerations since its discovery as an endogenously generated free radical. Nonetheless, the impacts of this signaling molecule can be seemingly contradictory, being both pro-and antitumorigenic, which complicates the development of cancer treatments based on the modulation of NO fluxes in tumors. At a fundamental level, low levels of NO drive oncogenic pathways, immunosuppression, metastasis, and angiogenesis, while higher levels lead to apoptosis and reduced hypoxia and also sensitize tumors to conventional therapies. However, clinical outcome depends on the type and stage of the tumor as well as the tumor microenvironment. In this Viewpoint, the current understanding of the concentration, spatial, and temporal dependence of responses to NO is correlated with potential treatment and prevention technologies and strategies.

Background: There is a need to improve the treatment of prostate cancer (PCa) and reduce treatment side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy for low-risk low-volume localised PCa, which rapidly disrupts targeted tumour vessels. There is interest in expanding the use of VTP to higher-risk disease. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. FRT alters the tumour microenvironment and promotes transient 'vascular normalisation'. We hypothesised that multimodality therapy combining fractionated radiotherapy (FRT) and VTP could improve PCa tumour control compared against monotherapy with FRT or VTP., Methods: We investigated whether sequential delivery of FRT followed by VTP 7 days later improves flank TRAMP-C1 PCa tumour allograft control compared to monotherapy with FRT or VTP., Results: FRT induced 'vascular normalisation' changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast-enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival., Conclusion: Combining FRT and VTP may be a promising multimodal approach in PCa therapy. This provides proof-of-concept for this multimodality treatment to inform early phase clinical trials., (© 2021. The Author(s).)

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.