Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Guo, Dong; Tong, Yuru; Jiang, Xiaoming; Meng, Ying; Jiang, Hongfei; Du, Linyong; Wu, Qingang; Li, Shan; Luo, Shudi; Li, Min; Xiao, Liwei; He, Haiyan; He, Xuxiao; Yu, Qiujing; Fang, Jing; Lu, Zhimin

doi:10.1016/j.cmet.2022.08.002

Cited by 172 publications

(108 citation statements)

References 44 publications

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“…The first step of glycolysis is catalyzed by hexokinase (HK), which converts glucose to glucose-6-phosphate (G-6-P). Recent studies have shown that HK2 can promote tumour immune evasion by phosphorylating IκBα, leading to the degradation of IκBα, activation of the NF-κB signalling pathway, and elevated PD-L1 expression levels [ 26 ]. We showed that CSFV infection inhibits the rate of extracellular acidification and reduces the overall cellular glycolysis level.…”

Section: Resultsmentioning

confidence: 99%

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

Song

Zhao

et al. 2023

Emerging Microbes & Infections

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CSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodelling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signalling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signalling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signalling pathway, NF-κB signalling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signalling pathway, NF-κB signalling pathway, and apoptosis.

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Section: Resultsmentioning

confidence: 99%

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

Song

Zhao

et al. 2023

Emerging Microbes & Infections

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“…Recent studies demonstrated that increased lactic acid in the TME could suppress anticancer immune cells by disturbing their intracellular pH ( Frauwirth et al, 2002 ; Gottfried et al, 2006 ) and impair T cell proliferation and cytokine production ( Brand et al, 2016 ; Fischer et al, 2007 ). Furthermore, Guo et al (2022) revealed that tumor immune evasion can be directly regulated by availability of glucose in the TME. When cancer glycolytic activity competes with immune cells for glucose uptake ( Husain et al, 2013a ; Husain, Seth & Sukhatme, 2013b ), cancer cells could effectively achieve immune evasion.…”

Section: Discussionmentioning

confidence: 99%

OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma

Wang

Jiang

et al. 2022

PeerJ

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Background Mitochondrial fusion and fission were identified to play key roles during multiple biology process. Thus, we aim to investigate the roles of OPA1 in mitochondria fusion and immune evasion of non-small cell lung cancer cells. Methods The transcriptional activation of genes related to mitochondrial dynamics was determined by using multi-omics data in lung adenocarcinoma (LUAD). We elucidated the molecular mechanism and roles of OPA1 promoting lung cancer through single-cell sequencing and molecular biological experiments. Results Here, we found that copy number amplification of OPA1 and MFN1 were co-occurring and synergistically activated in tumor epithelial cells in lung cancer tissues. Both of OPA1 and MFN1 were highly expressed in LUAD tumor tissues and OPA1 high expression was associated with poor prognosis. In terms of mechanism, the damaged mitochondria activated the apoptotic signaling pathways, inducing cell cycle arrest and cell apoptosis. More interestingly, OPA1 deficiency damaged mitochondrial dynamics and further blocked the respiratory function to increase the sensitivity of tumor epithelial to CD8+ T cells in non-small cell lung cancer. Conclusions Our study demonstrated the high co-occurrence of copy number amplification and co-expression of OPA1 and MFN1 in LUAD tissue, and further revealed the contribution of OPA1 in maintaining the mitochondria respiratory function and the ability of immune evasion to CD8+ T cells of LUAD.

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“…In ovarian cancer, Tregs pretreated with 2-DG also alleviate the inhibition of effector T cell proliferation ( Xu et al, 2021b ). In addition, HK recently has been found to upregulate PD-L1 expression in cancer cells in an NF-κB-dependent pathway, and HK inhibitor Lonidamine has shown favorable cancer elimination in combination with anti-PD-1 therapy in mice model ( Guo et al, 2022 ). However, the severe systemic toxicity induced by HK inhibitors in clinical studies warrants further investigation ( Pouysségur et al, 2022 ).…”

Section: Available Glycolysis-targeted Therapiesmentioning

confidence: 99%

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

Chu

Tian

Yang

et al. 2022

Front. Cell Dev. Biol.

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Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development.

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Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Cited by 172 publications

References 44 publications

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

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Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Cited by 172 publications

References 44 publications

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

OPA1 supports mitochondrial dynamics and immune evasion to CD8+ T cell in lung adenocarcinoma

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

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OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma