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Metabolic reprogramming in the tumor microenvironment of liver cancer
Open accessAbstract
The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.
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“Reprogramming of liver microenvironment is a key feature of hepatocarcinogenesis, which encompasses but not limited to metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu [10, 46, 65, 66].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [65]
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“High levels of GLUT1 expression are also associated with poor prognosis in both HCC and iCCA [80–84].”
BackgroundAlternative macrophage activation and metabolism
Odegaard, J. I., & Chawla, A. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130138 · Cited by 640 · cited 1×
“On the other hand, macrophage polarization is tightly correlated with metabolic rearrangement [188].”
BackgroundThe gut microbiome and liver cancer: mechanisms and clinical translation
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“Emerging studies have addressed the pivotal roles of the gut microbiota in PLC pathogenesis and anti-tumor therapy [5, 193–196].”
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BackgroundSelf-citationWnt–β-catenin signalling in liver development, health and disease
Perugorria, M. J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marín, J. J. G., Bujanda, L., & Bañales, J. M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0075-9 · Cited by 622
Molecular and histological correlations in liver cancer
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“Concordantly, de novo lipogenesis gradually increases from normal liver tissue to liver tumors and is generally associated with advanced HCC and worse patient prognoses [49–52].”
BackgroundHuman gut bacteria produce ΤΗ17-modulating bile acid metabolites
Paik, D., Yao, L., Zhang, Y., Bae, S., D’Agostino, G. D., Zhang, M., Kim, E., Franzosa, E. A., Avila-Pacheco, J., Bisanz, J. E., et al. (2022) · Nature · doi:10.1038/s41586-022-04480-z · Cited by 594
Self-citationDisturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
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“The liver immune system precludes gut-derived microbes and corresponding metabolites without evoking a systemic immune response, thus demonstrating immune privilege [209, 210].”
BackgroundSuppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J. K., Green, E., Deumelandt, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0095-6 · Cited by 566 · cited 1×
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BackgroundZheng, Y., Wang, T., Tu, X., Huang, Y., Zhang, H., Tan, D., Jiang, W., Cai, S., Zhao, P., Song, R., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0650-9 · Cited by 550
Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer
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“Considering the critical role of Treg cells in immunotherapy, lactylation of MOESIN in Treg cells may predict the response of anti-PD-1 therapy in HCC [139].”
BackgroundOne-carbon metabolism in cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.118 · Cited by 525
Zhu, A. X., Macarulla, T. M., Javle, M. M., Kelley, R. K., Lubner, S. J., Adeva, J., Cleary, J. M., Catenacci, D. V. T., Borad, M. J., Bridgewater, J. A., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.3836 · Cited by 524
CD8+ T cells in the cancer-immunity cycle
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BackgroundTumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner
Holmgaard, R., Zamarin, D., Li, Y., Gasmi, B., Munn, D. H., Allison, J. P., Merghoub, T., & Wolchok, J. D. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.077 · Cited by 496 · cited 1×
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BackgroundBehary, J., Amorim, N. M. L., Jiang, X., Raposo, A. E., Gong, L., McGovern, E., Ibrahim, R., Chu, F., Stephens, C., Jebeili, H., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20422-7 · Cited by 483 · cited 2×
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“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
BackgroundChen, Y., Ramjiawan, R. R., Reiberger, T., Ng, M. R., Hato, T., Huang, Y., Ochiai, H., Kitahara, S., Unan, E. C., Reddy, T. P., et al. (2015) · Hepatology · doi:10.1002/hep.27665 · Cited by 451 · cited 1×
“Chen et al. proposed that sorafenib treatment increases intra-tumoral hypoxia, promoting immunosuppression through the stromal cell-derived factor 1α (SDF1α)-CXCR4 axis-induced Treg cells/M2φ accumulation in orthotopic HCC mouse models [152].”
BackgroundMetabolic Characterization of Hepatocellular Carcinoma Using Nontargeted Tissue Metabolomics
Huang, Q., Tan, Y., Yin, P., Ye, G., Gao, P., Lu, X., Wang, H., & Xu, G. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0308 · Cited by 420 · cited 2×
“Moreover, numerous studies indicate enhanced amino acid metabolism in liver tumors compared to non-tumor tissues [1, 31, 37, 60, 61].”
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“We and others have identified numerous putative driver genes that reshape PLC metabolism [29, 30, 75– 79] (Table 1).”
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“In MASH-associated HCC mouse models, neutrophil extra-cellular traps (NETs) interact with naïve CD4 + T cells to facilitate its mitochondrial OXPHOS through TLR4 expression, contributing to their differentiation into immunosuppressive Treg cells [180].”
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Gut microbiome in HCC – Mechanisms, diagnosis and therapy
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“Changes in the gut microbiome disturb immune cell infiltration and function in the tumor microenvironment (TME) of PLC, potentially affecting the efficacy of current immunotherapies [5].”
BackgroundGLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis
Amann, T., Maegdefrau, U., Hartmann, A., Agaimy, A., Marienhagen, J., Weiß, T. S., Stoeltzing, O., Warnecke, C., Schölmerich, J., Oefner, P. J., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080596 · Cited by 370 · cited 1×
“High levels of GLUT1 expression are also associated with poor prognosis in both HCC and iCCA [80–84].”
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The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis
Xu, D., Wang, Z., Xia, Y., Shao, F., Xia, W., Wei, Y., Li, X., Qian, X., Lee, J.-H., Du, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2183-2 · Cited by 360 · cited 1×
“Concordantly, de novo lipogenesis gradually increases from normal liver tissue to liver tumors and is generally associated with advanced HCC and worse patient prognoses [49–52].”
BackgroundInosine is an alternative carbon source for CD8+-T-cell function under glucose restriction
Wang, T., Gnanaprakasam, J. R., Chen, X., Kang, S., Xu, X., Sun, H., Liu, L., Rodgers, H., Miller, E., Cassel, T., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0219-4 · Cited by 343
Advances in PET imaging of cancer
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“Due to significant glucose uptake in PLC bulk tissues, 18 F-2-deoxyglucose ( 18 FDG) positron emission tomography (PET) imaging is widely used for PLC diagnosis and progression monitoring [14].”
BackgroundHan, S., Bao, X., Zou, Y., Wang, L., Li, Y., Yang, L., Liao, A., Zhang, X., Jiang, X. M., Liang, D., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg2697 · Cited by 328 · cited 1×
“Additionally, gut microbiome-derived metabolite D-lactate can shift TAMs from the M2 to M1 phenotype, remodeling the immunosuppressive TME in HCC mice [111, 228].”
BackgroundLipid alterations in chronic liver disease and liver cancer
Paul, B., Lewińska, M., & Andersen, J. B. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100479 · Cited by 326 · cited 1×
“High-cholesterol diets induce HCC in mice, partly through dysregulation of metabolism and calcium signaling [55–57].”
BackgroundMitochondrial fragmentation limits NK cell-based tumor immunosurveillance
Zheng, X., Qian, Y., Fu, B., Jiao, D., Jiang, Y., Chen, P., Shen, Y., Zhang, H., Sun, R., Tian, Z., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0511-1 · Cited by 316 · cited 1×
“Another study showed that hypoxic TME drives NK cell loss and dysfunction via mTOR-GTPase dynamin-related protein 1 (Drp1) mitochondrial fragmentation, leading to HCC immune evasion in human liver cancer and mouse liver models [106].”
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“Under glucose/glu-tamine-deprived conditions, overexpressed cMYC also activates the serine biosynthesis pathway to adopt metabolic switch through transcriptionally upregulated the final rate-limiting enzyme phosphoserine phosphatase in both HCC cell lines and xenograft mouse models [85].”
BackgroundArginine reprograms metabolism in liver cancer via RBM39
Mossmann, D., Müller, C., Park, S., Ryback, B. M., Colombi, M., Ritter, N., Weißenberger, D., Dazert, E., Coto‐Llerena, M., Nuciforo, S., et al. (2023) · Cell · doi:10.1016/j.cell.2023.09.011 · Cited by 309 · cited 1×
“Targeting RBM39 instead of circulating arginine may offer a way to reverse the oncogenic pathway triggered by high arginine pools in HCC cells, thereby avoiding the adverse side effects of circulating arginine-depleting therapy [63].”
BackgroundHalford, S. E. R., Veal, G. J., Wedge, S. R., Payne, G. S., Bacon, C. M., Sloan, P., Dragoni, I., Heinzmann, K., Potter, S., Salisbury, B. M., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2263 · Cited by 305
NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
Lv, H., Lv, G., Chen, C., Zong, Q., Jiang, G., Ye, D., Cui, X., He, Y., Xiang, W., Han, Q. Y., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.021 · Cited by 304 · cited 1×
“For instance, NAD + metabolism triggers PD-L1 expression on tumor cells, impairing the cytolytic activity of PD-1 + T cells through αKG-mediated epigenetic modifications [164].”
BackgroundOncometabolite d -2HG alters T cell metabolism to impair CD8 + T cell function
Notarangelo, G., Spinelli, J. B., Perez, E. M., Baker, G. J., Kurmi, K., Elia, I., Stopka, S. A., Baquer, G., Lin, J., Golby, A. J., et al. (2022) · Science · doi:10.1126/science.abj5104 · Cited by 298 · cited 1×
“Oncometabolites, such as lactic acid [102–114], kynurenine [115–117], adenosine [117], 2-HG [118, 119], and prostaglandin E2 (PGE2) [120], typically antagonize the anti-tumor immune response and/or promote the immunosuppressive activities of TME components, ultimately leading to immune evasion.”
BackgroundSelf-citationYang, X., Lu, Y., Hang, J., Zhang, J., Zhang, T., Huo, Y., Liu, J., Lai, S., Luo, D., Wang, L., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0111 · Cited by 289 · cited 1×
“Oncometabolites, such as lactic acid [102–114], kynurenine [115–117], adenosine [117], 2-HG [118, 119], and prostaglandin E2 (PGE2) [120], typically antagonize the anti-tumor immune response and/or promote the immunosuppressive activities of TME components, ultimately leading to immune evasion.”
BackgroundZhang, J., Zhang, Q., Lou, Y., Fu, Q., Chen, Q., Wei, T., Yang, J., Tang, J., Wang, J., Chen, Y., et al. (2018) · Hepatology · doi:10.1002/hep.29681 · Cited by 286 · cited 1×
“M2-like TAMs upregulate the glycolysis pathway under hypoxic TME and produce excessive IL1β to facilitate EMT and subsequent metastasis in HCC [190].”
BackgroundMao, J., Wang, D., Long, J., Xu, Y., Lin, J., Song, Y., Xie, F., Xun, Z., Wang, Y., Wang, Y., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003334 · Cited by 285
Self-citationAltorki, N., Keresztes, R., Port, J., Libby, D., Korst, R., Flieder, D., Ferrara, C. A., Yankelevitz, D., Subbaramaiah, K., Pasmantier, M., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.07.127 · Cited by 277 · cited 1×
“…isocitrate dehydrogenase IDH1/2 inhibitor Enasidenib/Ivosidenib (for 2-HG production) [124], and the cyclooxygenase COX-2 inhibitor Celecoxib (for PGE2 accumulation) [125, 126] are being evaluated or approved to target cancer metabolism, aiming to enhance the efficacies of current therapies [127].”
BackgroundRIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis
Wu, L., Zhang, X., Zheng, L., Zhao, H., Yan, G., Zhang, Q., Zhou, Y. J., Lei, J., Zhang, J., Wang, J., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0261 · Cited by 277 · cited 1×
“In mouse and human HCC, the serine/threonine kinase RIPK3 is downregulated in macrophages, leading to FAO-dominated M2φ polarization via the ROS/Cas-pase1/PPAR pathway [189].”
BackgroundGut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma
Zhang, Q., Ma, C., Duan, Y., Heinrich, B., Rosato, U., Diggs, L. P., Ma, L., Roy, S., Fu, Q., Brown, Z. J., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0304 · Cited by 266 · cited 2×
“This induces TLR4-dependent CXCL1 expression in hepatocytes, leading to the recruitment of CXCR2 + PMN-MDSC, and ultimately promoting an immunosuppressive TME [203].”
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Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade
Bonavita, E., Bromley, C. P., Jonsson, G., Pelly, V. S., Sahoo, S., Walwyn-Brown, K., Mensurado, S., Moeini, A., Flanagan, E., Bell, C. R., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.020 · Cited by 257 · cited 1×
“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
BackgroundDietary supplements and disease prevention — a global overview
Rautiainen, S., Manson, J. E., Lichtenstein, A. H., & Sesso, H. D. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.54 · Cited by 252 · cited 1×
“People often consume dietary supplements for health benifits [230].”
BackgroundMetabolic rearrangements in primary liver cancers: cause and consequences
Satriano, L., Lewińska, M., Rodrigues, P. M., Bañales, J. M., & Andersen, J. B. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0217-8 · Cited by 245 · cited 5×
“These risk factors may promote the initiation and progression of PLC through metabolic reprogramming [1, 23].”
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“Moreover, numerous studies indicate enhanced amino acid metabolism in liver tumors compared to non-tumor tissues [1, 31, 37, 60, 61].”
BackgroundPelly, V. S., Moeini, A., Roelofsen, L. M., Bonavita, E., Bell, C. R., Hutton, C., Blanco‐Gómez, A., Banyard, A., Bromley, C. P., Flanagan, E., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1815 · Cited by 230 · cited 1×
“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
BackgroundLiang, Q., Teoh, N., Xu, L., Pok, S., Li, X., Chu, E. S., Chiu, J., Dong, L., Arfianti, A., Haigh, W. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06931-6 · Cited by 229
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“Increasing evidence suggests that the gut microbiota modulates immune responses in the TME of PLC [5, 194, 203, 207, 208].”
BackgroundLowery, M. A., Burris, H. A., Jankú, F., Shroff, R. T., Cleary, J. M., Azad, N. S., Goyal, L., Maher, E. A., Gore, L., Hollebecque, A., et al. (2019) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(19)30189-x · Cited by 223
Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis
Handa, P., Thomas, S., Morgan‐Stevenson, V., Maliken, B. D., Gochanour, E. M., Boukhar, S., Yeh, M. M., & Kowdley, K. V. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.3a0318-108r · Cited by 222 · cited 1×
“Compared to M1φ, M2φ tends to polarize under low ferrous iron levels [132].”
BackgroundBayerl, F., Meiser, P., Donakonda, S., Hirschberger, A., Lacher, S. B., Pedde, A., Hermann, C. D., Elewaut, A., Knolle, M. A., Ramsauer, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.05.011 · Cited by 218 · cited 1×
“PGE2, a bioactive lipid generated from arachidonic acid, has recently been implicated in immune evasion through multiple mechanisms [145].”
BackgroundContreras‐Baeza, Y., Sandoval, P. Y., Alarcón, R., Galaz, A., Cortés‐Molina, F., Alegría, K., Baeza‐Lehnert, F., Arce‐Molina, R., Guequén, A., Flores, C. A., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009093 · Cited by 218 · cited 1×
“For instance, upregulated MCT4 expression in HCC cells contributes to lactate exportation and subsequent TME acidification, ultimately leading to CD8 + T-cell exhaustion and M2φ polarization [136–138].”
BackgroundLee, P.-C., Wu, C.-J., Hung, Y.-W., Lee, C. J., Chi, C.-T., Lee, I.-C., Yu-Lun, K., Chou, S.-H., Luo, J.-C., Hou, M.-C., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004779 · Cited by 217 · cited 1×
“Lee et al. suggested that Lachnoclostridium , along with ursodeoxycholic and ursocholic acids, produce better responses to ICB treatment in patients with unresectable HCC [229].”
BackgroundGut microbiota–derived short‐chain fatty acids regulate group 3 innate lymphoid cells in HCC
Hu, C., Xu, B., Wang, X., Wan, W., Lu, J., Kong, D., Jin, Y., You, W., Sun, H., Mu, X., et al. (2022) · Hepatology · doi:10.1002/hep.32449 · Cited by 214 · cited 1×
“Thus, combining acetate supplementation with PD-1 blockades significantly boosts anti-tumor immunity [227].”
BackgroundHu, B., Yu, M., Ma, X., Sun, J., Liu, C., Wang, C., Wu, S., Fu, P., Yang, Z. F., He, Y., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1022 · Cited by 213 · cited 1×
“The consequent accumulation of glucose in the TME stimulates the expression of the costimulatory molecule CD27 via mTOR–FOXM1 signaling in CD8 + T cells, thereby reinforcing the functions of cytotoxic T cells in both immunocompetent orthotopic and spontaneous HCC models [131].”
BackgroundBidkhori, G., Benfeitas, R., Klevstig, M., Zhang, C., Nielsen, J., Uhlén, M., Borén, J., & Mardinoğlu, A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1807305115 · Cited by 212 · cited 2×
“…retrieved from several public datasets, genome-wide metabolic models (GEMs) stratified HCC patients into three prognostic subgroups with significant differences in dysregulated kynurenine metabolism (iHCC1), WNT/β-catenin-related lipid metabolism (iHCC2), and PI3K/AKT/mTOR signaling (iHCC3) [24].”
BackgroundQin, W.-H., Yang, Z.-S., Li, M., Chen, Y., Zhao, X.-F., Qin, Y.-Y., Song, J.-Q., Wang, B.-B., Yuan, B., Cui, X.-L., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.028 · Cited by 209 · cited 1×
“Of note, high serum cholesterol levels drive NK cell accumulation and subsequent lipid raft formation, further enhancing the anti-tumor activity in both DEN-induced HCC mouse models and Hepa1-6 (mouse hepatoma) subcutaneous models [184].”
BackgroundHuang, H., Ren, Z., Gao, X., Hu, X., Zhou, Y. M., Jiang, J., Lu, H., Yin, S., Ji, J., Zhou, L., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00796-5 · Cited by 200 · cited 1×
“Multi-omics studies incorporating 16S rRNA MiSeq sequencing in different cohorts from various regions of China have also identified gut microbes as non-invasive biomarkers for the early diagnosis of PLC [204–206].”
BackgroundLoss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis
Sun, R., Zhang, Z., Bao, R., Guo, X., Gu, Y., Yang, W., Wei, J., Chen, X., Tong, L., Meng, J., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.02.030 · Cited by 190 · cited 1×
“Sun et al. reported that SIRT5 expression is repressed in tumor cells, which leads to aberrant BA biosynthesis in the peroxisome and subsequent M2φ-induced immunosuppression in oncogene-induced HCC mouse models [144].”
BackgroundJia, X., Lu, S., Zeng, Z., Liu, Q., Dong, Z., Chen, Y., Zhu, Z., Hong, Z., Zhang, T., Du, G., et al. (2019) · Hepatology · doi:10.1002/hep.30852 · Cited by 184
Deng, H., Kan, A., Lyu, N., He, M. X., Huang, X., Qiao, S., Li, S., Lu, W., Xie, Q., Chen, H., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002305 · Cited by 181 · cited 1×
“Simultaneously, tumor-derived lactate induces programmed cell death ligand 1 (PD-L1) expression in infiltrated neutrophils through the MCT1/NF-κB/COX-2 pathway, thus counteracting the efficacy of lenvatinib monotherapy in HCC mouse models [142].”
BackgroundDinardo, C. D., Stein, A. S., Stein, E. M., Fathi, A. T., Frankfurt, O., Schuh, A. C., Döhner, H., Martinelli, G., Patel, P. A., Raffoux, E., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.01632 · Cited by 180 · cited 1×
“…inhibitor Oleclumab (for adenosine conversion) [123], the isocitrate dehydrogenase IDH1/2 inhibitor Enasidenib/Ivosidenib (for 2-HG production) [124], and the cyclooxygenase COX-2 inhibitor Celecoxib (for PGE2 accumulation) [125, 126] are being evaluated or approved to target cancer…”
BackgroundMetabolic reprogramming in cholangiocarcinoma
Raggi, C., Taddei, M. L., Rae, C. J., Braconi, C., & Marra, F. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.04.038 · Cited by 179 · cited 1×
“Leveraging genetically engineered mouse models of iCCA, IDH mutations were shown to increase the production of D-2-hydroxyglutarate (D-2-HG), affecting α-ketoglutarate (αKG)-dependent dioxygenases involved in DNA repair and epigenetic remodeling [92].”
Lipid Metabolic Reprogramming in Hepatocellular Carcinoma
Nakagawa, H., Hayata, Y., Kawamura, S., Yamada, T., Fujiwara, N., & Koike, K. (2018) · Cancers · doi:10.3390/cancers10110447 · Cited by 176 · cited 1×
“Lipid metabolic pathways, including fatty acid synthase (FASN) and stearoyl-COA desaturase (SCD) signaling, also sustain cancer stem cells in HCC, contributing to metastasis and drug resistance [54].”
BackgroundOGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism
Dai, W., Xu, L., Yu, X., Zhang, G., Guo, H., Liu, H., Song, G., Weng, S., Dong, L., Zhu, J., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.12.015 · Cited by 174 · cited 1×
“Glutamine, the most abundant amino acid in human blood, is a key carbon source for de novo lipogenesis in mitochondrial dysfunctional HCC [64].”
BackgroundFang, Y., Liu, W., Tang, Z., Ji, X. L., Zhou, Y., Song, S., Tian, M., Tao, C., Huang, R., Zhu, G., et al. (2022) · Hepatology · doi:10.1002/hep.32348 · Cited by 170
Chen, D., Ning, W.-R., Jiang, Z.-Z., Peng, Z.-P., Zhu, L., Zhuang, S., Kuang, D., Zheng, L., & Wu, Y. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.04.007 · Cited by 170 · cited 1×
“Chen et al. proposed that tumor-derived hyaluronan (HA) fragments induce aerobic glycolysis in monocytes and upregulate PD-L1 expression through the PFKFB3-NF-κB pathway [185].”
BackgroundZhu, Q., Zhou, L., Yang, Z., Lai, M.-C., Xie, H., Wu, L., Xing, C., Zhang, F., & Zheng, S. (2011) · Medical Oncology · doi:10.1007/s12032-011-9912-1 · Cited by 168
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“Thus, blocking CD47 on the cell surface enhances NK cell-mediated anti-tumor immunity in the hypoxic microenvironment of HCC [155].”
BackgroundLipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma
Hall, Z., Chiarugi, D., Charidemou, E., Leslie, J., Scott, E., Pellegrinet, L., Allison, M., Mocciaro, G., Anstee, Q. M., Evan, G. I., et al. (2020) · Hepatology · doi:10.1002/hep.31391 · Cited by 164 · cited 1×
“High-cholesterol diets induce HCC in mice, partly through dysregulation of metabolism and calcium signaling [55–57].”
BackgroundHypoxia‐driven immunosuppression by Treg and type‐2 conventional dendritic cells in HCC
Suthen, S., Lim, C. J., Nguyen, P. H. D., Dutertre, C., Lai, H. L. H., Wasser, M., Chua, C. J. H., Lim, T. K. H., Leow, W. Q., Loh, T. J., et al. (2022) · Hepatology · doi:10.1002/hep.32419 · Cited by 161 · cited 1×
“Subsequently, in vitro assays demonstrated that the direct interaction of infiltrated Treg cells with cDC2 mediates HLA-DR loss, a critical antigen presentation molecule required for anti-tumor T-cell activation [153].”
Backgroundβ-catenin-activated hepatocellular carcinomas are addicted to fatty acids
Senni, N., Savall, M., Granados, D. C., Alves‐Guerra, M., Sartor, C., Lagoutte, I., Gougèlet, A., Terris, B., Gilgenkrantz, H., Perret, C., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-315448 · Cited by 160 · cited 1×
“Wnt-β-catenin signaling is often hyperactivated, promoting PLC growth and dissemination [88]. β-catenin (encoded by CTNNB1 ) oncogenic activation in HCC cells induces FAO through the transcription factor peroxisome proliferator-activated receptor α (PPARα) [89].”
BackgroundWu, M., Shi, L., Dubrot, J., Merritt, J., Vijay, V., Wei, T.-Y., Kessler, E., Olander, K. E., Adil, R., Pankaj, A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1077 · Cited by 158 · cited 1×
“Consequently, the IDH1/2 inhibitor AG120 synergizes with ICBs for advancing immunotherapy in the treatment of mIDH1-driven genetically engineered mouse models [165].”
BackgroundAdebayo Michael, A. O., Ko, S., Tao, J., Moghe, A., Yang, H., Xu, M., Russell, J. O., Pradhan-Sundd, T., Liu, S., Singh, S., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.002 · Cited by 155 · cited 2×
“Glutamine addiction in glutamine synthetase (GS)-overexpressing HCC supports mTOR-dependent cell proliferation and survival in clinically relevant HCC models [65].”
BackgroundGCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment
Missiaen, R., Anderson, N. M., Kim, L. C., Nance, B., Burrows, M., Skuli, N., Carens, M., Riscal, R., Steensels, A., Li, F., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.06.010 · Cited by 154 · cited 1×
“Thus, combining GCN2 inhibition with senolytic agents could be an effective treatment strategy in arginine-deprived HCC cells [62].”
BackgroundIdentification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma
Nwosu, Z. C., Megger, D. A., Hammad, S., Sitek, B., Roessler, S. K., Ebert, M. P. A., Meyer, C., & Dooley, S. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.05.004 · Cited by 154 · cited 3×
“Moreover, numerous studies indicate enhanced amino acid metabolism in liver tumors compared to non-tumor tissues [1, 31, 37, 60, 61].”
BackgroundMcDonald, B., Zucoloto, A. Z., Yu, I.-L., Burkhard, R., Brown, K., Geuking, M. B., & McCoy, K. D. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.07.014 · Cited by 152 · cited 1×
“Additionally, gut microbiome-derived metabolite D-lactate can shift TAMs from the M2 to M1 phenotype, remodeling the immunosuppressive TME in HCC mice [111, 228].”
BackgroundWang, M., Wu, H., Fu, G., Zhang, H., Zhou, X., Tang, L., Dong, L., Qin, C., Huang, S., Zhao, L., et al. (2015) · Hepatology · doi:10.1002/hep.28415 · Cited by 149
Wabitsch, S., McCallen, J., Kamenyeva, O., Ruf, B., McVey, J. C., Kabát, J., Walz, J. S., Rotman, Y., Bauer, K. C., Craig, A. J., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.010 · Cited by 147 · cited 1×
“This impairment diminishes the efficacy of ICB therapy, which could be salvaged by metformin [182].”
BackgroundXu, M., Zhou, C., Weng, J., Chen, Z., Zhou, Q., Gao, J., Shi, G., Ke, A., Ren, N., Sun, H., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02458-3 · Cited by 145 · cited 1×
“For instance, upregulated MCT4 expression in HCC cells contributes to lactate exportation and subsequent TME acidification, ultimately leading to CD8 + T-cell exhaustion and M2φ polarization [136–138].”
BackgroundPharmaco-proteogenomic characterization of liver cancer organoids for precision oncology
Ji, S., Li, F., Fu, Z., Wu, G., Wu, Y. C., Lin, Y., Lu, D., Song, Y., Cui, P., Yang, Z., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adg3358 · Cited by 142 · cited 1×
“Glucose-6-phosphate dehydrogenase (G6PD) was identified as a potential target in the subtype with an enriched drug metabolism pathway, consistent with the previous results [32–35].”
ResultSelf-citationMurai, H., Kodama, T., Maesaka, K., Tange, S., Motooka, D., Suzuki, Y., Shigematsu, Y., Inamura, K., Mise, Y., Saiura, A., et al. (2022) · Hepatology · doi:10.1002/hep.32573 · Cited by 141 · cited 1×
“Multi-omics study showed lipid accumulation in HCC elevates PD-L1 expression, inducing an immunosuppressive TME [28].”
BackgroundMetabolic reprogramming and its clinical implication for liver cancer
Yang, F., Hilakivi-Clarke, L. A., Shaha, A., Wang, Y., Wang, X., Deng, Y., Lai, J., & Kang, N. (2023) · Hepatology · doi:10.1097/hep.0000000000000005 · Cited by 140 · cited 1×
“It has been demonstrated that liver cancer cells typically utilize glycolysis under hypoxic conditions to produce lactate via lactic dehydrogenase (LDH) [38].”
BackgroundLiu, J., Geng, W., Sun, H., Liu, C., Huang, F., Cao, J., Xia, L., Zhao, H., Zhai, J., Li, Q., et al. (2021) · Gut · doi:10.1136/gutjnl-2021-325189 · Cited by 140 · cited 1×
“This gut–liver axis executes critical functions in nutrient metabolism and bacterial metabolite clearance, mainly through the portal vein [192].”
BackgroundChaudagar, K., Hieromnimon, H. M., Khurana, R., Labadie, B., Hirz, T., Mei, S., Hasan, R., Shafran, J. S., Kelley, A., Apostolov, E., et al. (2022) · bioRxiv · doi:10.1101/2022.05.12.490223 · Cited by 138
Ding, Z., Ericksen, R. E., Escande‐Beillard, N., Lee, Q. Y., Loh, A., Denil, S. L. I. J., Steckel, M., Haegebarth, A., Ho, T. S. W., Chow, P. K. H., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.10.026 · Cited by 138 · cited 1×
“Additionally, the glutamate-to-proline biosynthetic flux is elevated in tumor tissues, promoting HCC cell proliferation and tumor growth in both tumor models and regenerating tissues [66].”
BackgroundChu, Q. S.-C., Sangha, R. S., Spratlin, J. L., Vos, L. J., Mackey, J. R., McEwan, A. J. B., Venner, P. M., & Michelakis, E. D. (2015) · Investigational New Drugs · doi:10.1007/s10637-015-0221-y · Cited by 137
Lü, M., Lu, L., Dong, Q., Yu, G., Chen, J., Qin, L., Wang, L.-X., Zhu, W., & Jia, H. (2018) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmy009 · Cited by 134 · cited 1×
“Other glucose metabolic pathways, such as the pentose phosphate pathway (PPP) and the hexosamine biosynthetic pathway (HBP), are also more active in HCC tissue compared to normal adjacent tissues [44–47] (Fig.”
BackgroundTumor-Derived Adenosine Promotes Macrophage Proliferation in Human Hepatocellular Carcinoma
Wang, J., Wang, Y., Chu, Y., Li, Z., Yu, X., Huang, Z., Xu, J., & Zheng, L. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2020.10.021 · Cited by 133 · cited 1×
“Tumor cell-derived adeno - sine also synergizes with autocrine granulocyte–macrophage colony-stimulating factor (GM-CSF) secreted from activated TAM to promote their proliferation, thus maintaining the Mφ pools in HCC [151].”
BackgroundPeng, Z.-P., Jiang, Z.-Z., Guo, H.-F., Zhou, M., Huang, Y., Ning, W.-R., Huang, J., Zheng, L., & Wu, Y. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.05.004 · Cited by 128 · cited 1×
“These processes ultimately lead to the metastasis of HCC, as shown by both ex vivo and in vitro experiments [186].”
BackgroundNonalcoholic Fatty Liver Disease and the Gut-Liver Axis: Exploring an Undernutrition Perspective
Bauer, K. C., Littlejohn, P. T., Ayala, V., Creus-Cuadros, A., & Finlay, B. B. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.01.058 · Cited by 127
Lercher, A., Bhattacharya, A., Popa, A., Caldera, M., Schlapansky, M. F., Baazim, H., Agerer, B., Gürtl, B., Kosack, L., Májek, P., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.10.014 · Cited by 124 · cited 1×
“…activates hepatocyte-intrinsic type I interferon (IFN-I) responses to break the urea cycle, leading to decreased arginine/ ornithine ratios in the circulation and subsequently suppressed virus-specific CD8 + T-cell responses in chronic lymphocytic choriomeningitis virus (LCMV)-infected mice [148].”
BackgroundHong, X.-H., Song, R.-P., Song, H.-W., Zheng, T., Wang, J.-B., Liang, Y.-J., Qi, S., Lu, Z., Song, X., Jiang, H.-C., et al. (2013) · Gut · doi:10.1136/gutjnl-2013-305302 · Cited by 123
Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments
Miller, A., Nagy, C., Knapp, B., Laengle, J., Ponweiser, E., Gröger, M., Starkl, P. M., Bergmann, M. M., Wagner, O. F., & Haschemi, A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.014 · Cited by 123 · cited 1×
“With the advent of immunome-tabolism in cancer treatment [18–22], greater attention should be given to the interplay of metabolism-related immune signaling.”
BackgroundZhou, P., Chang, W.-Y., Gong, D.-A., Xia, J. L., Chen, W., Huang, L., Liu, R., Liu, Y., Chen, C., Wang, K., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.09.009 · Cited by 122 · cited 1×
“…mechanism showed that microbiota-derived acetate enhanced UDP-GlcNAc biosynthesis and O-GlcNAcylation, and hyper-O-GlcNAcylation of eukaryotic elongation factor 1A1 (eEF1A1) at T279 promoted the proliferation of tumor cells and HCC progression in the DEN + CCl 4 -induced HCC mouse model [200].”
BackgroundPhoomak, C., Vaeteewoottacharn, K., Silsirivanit, A., Saengboonmee, C., Seubwai, W., Sawanyawisuth, K., Wongkham, C., & Wongkham, S. (2017) · Scientific Reports · doi:10.1038/srep43842 · Cited by 122 · cited 1×
“Other glucose metabolic pathways, such as the pentose phosphate pathway (PPP) and the hexosamine biosynthetic pathway (HBP), are also more active in HCC tissue compared to normal adjacent tissues [44–47] (Fig.”
BackgroundGLUT1 and ASCT2 as Predictors for Prognosis of Hepatocellular Carcinoma
Sun, H.-W., Yu, X.-J., Wu, W., Chen, J., Shi, M., Zheng, L., & Xu, J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0168907 · Cited by 121
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“Thus, HCC mouse models derived from the F1 subtype are responsive to anti-PD-1 (programmed cell death protein 1) therapy, in contrast with mouse models derived from the F2 and F3 subtypes [36].”
BackgroundHypoxia-induced macropinocytosis represents a metabolic route for liver cancer
Zhang, M. S., Cui, J. D., Lee, D., Yuen, V. W., Chiu, D. K., Goh, C. C., Cheu, J. W., Tse, A. P., Bao, M. H., Wong, B. P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28618-9 · Cited by 109 · cited 1×
“Hypoxia also induces micropinocytosis for nutrient scavenging via the hypoxia-inducible factor (HIF)/EH domain-containing protein 2 (EHD2) pathways in several HCC cell lines and mouse models [43].”
BackgroundSelf-citationKotsiliti, E., Leone, V., Schuehle, S., Govaere, O., Li, H., Wolf, M. J., Horvatic, H., Bierwirth, S., Hundertmark, J., Inverso, D., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.04.037 · Cited by 108 · cited 1×
“Meanwhile, gastrointestinal IgA + metabolically activated B cells can license auto-aggressive T cells, promoting HCC development in an antigen-independent manner in MASH-induced HCC mouse models [183].”
BackgroundSLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma
Kim, Y. H., Jeong, D. C., Pak, K., Han, M., Kim, J., Liu, L., Kim, H. J., Kim, T. W., Kim, T. H., Hyun, D. W., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20266 · Cited by 105
Che, Y., Chen, G., Guo, Q., Duan, Y., Feng, H., & Xia, Q. (2023) · Hepatology · doi:10.1097/hep.0000000000000047 · Cited by 105 · cited 1×
“Butyrate accumulation disrupts intracellular calcium homeostasis and induces the production of ROS, thus improving the efficacy of TKI therapy in HCC mouse models [202].”
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Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis
Zhao, J., Ye, Y., Gao, C.-C., Wang, L., Ren, K., Jiang, R., Hu, S., Liang, S.-Q., Bai, J., Liang, J.-L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110451 · Cited by 101
Jouve, J., Lecomte, T., Bouché, O., Barbier, E., Akouz, F. K., Riachi, G., Khac, É. N., Ollivier-Hourmand, I., Debette-Gratien, M., Faroux, R., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.04.021 · Cited by 99
G6PD: A hub for metabolic reprogramming and redox signaling in cancer
Yang, H., Stern, A., & Chiu, D. T.-Y. (2020) · Biomedical Journal · doi:10.1016/j.bj.2020.08.001 · Cited by 99
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“Moreover, numerous studies indicate enhanced amino acid metabolism in liver tumors compared to non-tumor tissues [1, 31, 37, 60, 61].”
BackgroundLu, L.-G., Zhou, Z.-L., Wang, X.-Y., Liu, B., Lu, J.-Z., Liu, S., Zhang, G.-B., Zhan, M.-X., & Chen, Y. (2022) · Gut · doi:10.1136/gutjnl-2021-326350 · Cited by 98 · cited 1×
“Furthermore, the PKM2/HIF-1α axis in human HCC samples and syngeneic mouse models drives fibronectin 1 (FN1) production to instigate pluripotent polarization of macrophages, concurrent with anti-tumorigenic IL-12p70 production from glycolytic macrophages [191].”
BackgroundFaloppi, L., Scartozzi, M., Bianconi, M., Svegliati‐Baroni, G., Toniutto, P., Giampieri, R., Prete, M. D., Minicis, S. D., Bitetto, D., Loretelli, C., et al. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-110 · Cited by 97
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“In MASH-related HCC mouse models, the androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), combined with obesity-induced IL-6/STAT3 signaling, induces lipid metabolic reprogramming and MDSC-dominated immunosuppression [161].”
BackgroundNelson, M. E., Lahiri, S., Chow, J. D. Y., Byrne, F. L., Hargett, S. R., Breen, D. S., Olzomer, E. M., Wu, L. E., Cooney, G. J., Turner, N. A., et al. (2017) · Nature Communications · doi:10.1038/ncomms14689 · Cited by 93 · cited 1×
“This discrepancy may be attributed to differences between clinical samples and preclinical models of HCC, highlighting the need for a thorough exploration of tumor-driving events and metabolic plasticity [53].”
BackgroundYang, Z.-S., Qin, W., Chen, Y., Yuan, B., Song, X.-L., Wang, B., Shen, F., Fu, J., & Wang, H.-Y. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.04.038 · Cited by 91 · cited 1×
“Conversely, high serum cholesterol levels are linked with better patient outcomes by inhibiting tumor metastasis [59], implying that cholesterol distribution and homeostasis significantly influence HCC tumorigenesis (Fig.”
BackgroundFu, Y., Mackowiak, B., Feng, D., Lu, H., Guan, Y., Lehner, T., Pan, H., Wang, X. W., He, Y., & Gao, B. (2023) · Gut · doi:10.1136/gutjnl-2022-327924 · Cited by 86 · cited 1×
“This results in adenosine-mediated immunosuppressive roles on T cells and myeloid cells [149, 150].”
BackgroundPhase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma
Davar, D., Wang, H., Chauvin, J.-M., Pagliano, O., Fourcade, J. J., Ka, M., Menna, C., Rose, A., Sander, C., Borhani, A. A., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.18.00632 · Cited by 86 · cited 1×
“The results of a recent clinical trial demonstrated the promising efficacy of combined IFNα and ICB therapy in patients with advanced melanoma [130].”
BackgroundLin, J., Dai, Y., Sang, C., Song, G., Xiang, B., Zhang, M., Dong, L., Xia, X., Ma, J., Shen, X., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004892 · Cited by 86 · cited 1×
“This results in an immunosuppressive TME dominated by excessive neutrophil infiltration and contributes to poor prognosis in iCCA [147].”
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NeuCode Proteomics Reveals Bap1 Regulation of Metabolism
Baughman, J. M., Rose, C. M., Kolumam, G., Webster, J. D., Wilkerson, E. M., Merrill, A. E., Rhoads, T. W., Noubade, R., Katavolos, P., Lesch, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.096 · Cited by 73 · cited 2×
“We and others have identified numerous putative driver genes that reshape PLC metabolism [29, 30, 75– 79] (Table 1).”
BackgroundLin, M., Lv, D., Zheng, Y., Wu, M., Xu, C., Zhang, Q., & Wu, L. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s163266 · Cited by 73 · cited 1×
“In high-fat diet (HFD)-induced HCC, or steatohepa-titic HCC, the fatty acid oxidation (FAO) pathway tends to be downregulated to protect HCC cells from lipotox-icity [48].”
BackgroundGlycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth
Mukha, D., Fokra, M., Feldman, A., Sarvin, B., Sarvin, N., Nevo-Dinur, K., Besser, E., Hallo, E., Aizenshtein, E., Schug, Z. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.04.006 · Cited by 69 · cited 1×
“In HCC cells, glycine-derived 1C units support purine and pyrimidine biosynthesis and tumor progression through glycine cleavage system (GCS) flux [73].”
BackgroundThe gut–liver axis: host microbiota interactions shape hepatocarcinogenesis
Silveira, M. A. D., Bilodeau, S., Greten, T. F., Wang, X. W., & Trinchieri, G. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.02.009 · Cited by 69 · cited 1×
“Increasing evidence suggests that the gut microbiota modulates immune responses in the TME of PLC [5, 194, 203, 207, 208].”
BackgroundWang, N., Tan, H., Lu, Y., Chan, Y.-T., Wang, D., Guo, W., Xu, Y., Zhang, C., Chen, F., Tang, G., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00485-8 · Cited by 68 · cited 1×
“Meanwhile, PIWIL1 regulates the secretion of Complement C3 to mediate interaction between HCC cells and MDSC, promoting the immunosuppressive cytokine IL10 in the TME [162].”
BackgroundNing, W.-R., Jiang, D., Liu, X.-C., Huang, Y.-F., Peng, Z.-P., Jiang, Z.-Z., Kang, T., Zhuang, S.-M., Wu, Y., & Zheng, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci153110 · Cited by 66 · cited 1×
“This production promotes epithelial-mesenchymal transition (EMT) and HCC metastasis [187].”
BackgroundHypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development
Cheu, J. W.-S., Chiu, D. K.-C., Kwan, K. K.-L., Yang, C., Yuen, V. W.-H., Goh, C. C., Chui, N. N.-Q., Shen, W., Law, C.-T., Li, Q., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade5111 · Cited by 65 · cited 1×
“This results in adenosine-mediated immunosuppressive roles on T cells and myeloid cells [149, 150].”
BackgroundSelf-citationDietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA
Li, J., Yang, H. Z., Lei, M., Zhu, W., Su, Y., Li, K.-Y., Zhu, W.-Y., Wang, J., Zhang, L., Qu, J., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01017-8 · Cited by 63 · cited 1×
“Recent findings have also highlighted the promotion of tumor development by dietary folate supplementation through the integration of methionine and 1C metabolism in the HCC mouse model induced by DEN/HFD [74].”
BackgroundProteogenomic characterization of cholangiocarcinoma
Deng, M., Ran, P., Chen, L., Wang, Y., Yu, Z., Cai, K., Feng, J., Qin, Z., Yin, Y., Tan, S., et al. (2022) · Hepatology · doi:10.1002/hep.32624 · Cited by 61
Antonarakis, E., Heath, E., Walczak, J. R., Nelson, W., Fedor, H., Marzo, A. D. D., Zahurak, M., Piantadosi, S., Dannenberg, A., Gurganus, R., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.21.9410 · Cited by 60 · cited 1×
“…isocitrate dehydrogenase IDH1/2 inhibitor Enasidenib/Ivosidenib (for 2-HG production) [124], and the cyclooxygenase COX-2 inhibitor Celecoxib (for PGE2 accumulation) [125, 126] are being evaluated or approved to target cancer metabolism, aiming to enhance the efficacies of current therapies [127].”
BackgroundSun, J., Zhang, N., Xu, R.-C., Zhang, G., Liu, Z., Abuduwaili, W., Wang, F., Yu, X., Shi, X., Song, G., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-03034-7 · Cited by 60 · cited 1×
“This iron competition culminates in an M2-like TAM polarization in vitro [133].”
BackgroundHalford, S. E. R., Jones, P. S., Wedge, S. R., Hirschberg, S., KATUGAMPOLA, S. D., Veal, G. J., Payne, G. S., Bacon, C. M., Potter, S., Griffin, M., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.35.15_suppl.2516 · Cited by 59 · cited 1×
“Currently, the monocarboxylate transporter MCT1 inhibitor AZD3965 (for lactate sym-porter) [121], the indoleamine 2,3-dioxygenase IDO1 inhibitor Indoximod/Epacadostat (for kynurenine synthesis) [122], the CD73 inhibitor Oleclumab (for adenosine conversion) [123], the isocitrate dehydrogenase IDH1/2…”
BackgroundXing, X., Hu, E., Ouyang, J., Zhong, X., Wang, F., Liu, K., Cai, L., Zhou, Y., Wang, Y., Chen, G., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101315 · Cited by 59 · cited 1×
“Multi-omics studies have nominated metabolic pathways as the most dramatic alterations in HCC and iCCA, compared with normal adjacent tissues [26–29].”
BackgroundWong, A. M., Ding, X., Wong, A. M. G., Xu, M., Zhang, L., Leung, H. H. W., Chan, A. W. H., Song, Q. X., Kwong, J., Chan, L. K., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.015 · Cited by 58 · cited 1×
“This shift in the driver mutations results in immune exclusion through the repression of the TNF receptor superfamily member 19 (TNFRSF19)- mediated senescence-associated secretory phenotype (SASP), as shown in a syngeneic immunocompetent mouse model [157].”
BackgroundLi, Y., Mo, H., Wu, S., Liu, X., & Tu, K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.801959 · Cited by 55 · cited 1×
“The well-known “Warburg effect” rearranges glucose metabolism to produce excessive lactic acid, which has emerged as an important regulator in promoting immune evasion in PLC [134, 135].”
Background
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Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133
The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy
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“Unlike normal cells, cancer cells undergo metabolic reprogramming to meet the increased demands for energy, macromolecule biosynthesis, and redox balance [16, 17].”
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“Moreover, interfering glucose metabolic pathways, including OXPHOS, glycolysis and PPP, can also disrupt glucose metabolic process, thus inducing glucose dyshomeo-stasis [28,29].”
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“Reprogramming of liver microenvironment is a key feature of hepatocarcinogenesis, which encompasses but not limited to metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu [10, 46, 65, 66].”
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Metadata
- Authors
- Lin, J., Rao, D., Zhang, M., & Gao, Q.
- Affiliations
- Fudan University (CN)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Gao, Qiang
- Venue
- Journal of Hematology & Oncology
- Published
- 2024-01-31
- Volume
- 17
- Issue
- 1
- Pages
- 6-6
- ISSN
- 1756-8722 (ISSN-L)
- PMC
- PMC10832230
- OpenAlex
- W4391404272
- Cited by
- 251
- References
- 231
- Citations by year
- 2026: 125 · 2025: 110 · 2024: 16
- FWCI
- 12.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Hematology & Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82103314, 82130077)
- Jinshan Hospital Flexible Mobile Talent Research Startup Fund (RXRC-2020-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- metabolic reprogramming, liver cancer, tumor microenvironment, tumor immune microenvironment, cancer immunotherapy, immunotherapy resistance, gut-liver axis, immune surveillance, immune evasion
- MeSH terms
- Metabolic Reprogramming, Energy Metabolism, Glycolysis, Humans, Immunotherapy, Liver Neoplasms, Neoplasms, Tumor Microenvironment
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