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 the liver microenvironment is a key feature of hepatocarcinogenesis, encompassing metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu.
“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]
The Background and the section on metabolic reprogramming of immune cells describe metabolic changes in liver tumors and immune cells, including changes in inflammatory signaling. The passages do not support the specific claim that fetal-associated endothelial cells re-emerge; a search for that term found no supporting passage. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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“High levels of GLUT1 expression are also associated with poor prognosis in both HCC and iCCA [80–84].”
BackgroundMetabolomics in cancer research and emerging applications in clinical oncology
Schmidt, D. R., Patel, R., Kirsch, D. G., Lewis, C. A., Heiden, M. G. V., & Locasale, J. W. (2021) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21670 · Cited by 652 · cited 1× · see citing works
“Tumor cells often exhibit a high dependence on a reprogrammed metabolic state for stress adaptation and infinite proliferation, which can be leveraged for non-invasive cancer diagnosis [6–8].”
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× · see citing works
“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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“…tumor progression, lactate accumulation also causes lactylation of adenylate kinase 2 (AK2) at K28, compromising its kinase activity and disrupting energy homeostasis in HCC cells, thereby facilitating tumor proliferation, invasion, and metastasis as shown in several xenograft mouse models [39].”
BackgroundSelf-citationWnt–β-catenin signalling in liver development, health and disease
Perugorria, M. J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marı́n, J. J. G., Bujanda, L., & Bañales, J. M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0075-9 · Cited by 606 · see citing works
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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].”
BackgroundMolecular and histological correlations in liver cancer
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“Consistent with the histological features [25], both iHCC1 and iHCC2 exhibit hepatocyte differentiation and maturation, whereas iHCC3 is associated with proliferation and immune activation [24].”
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 · see citing works
Self-citationDisturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
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Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
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“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.”
BackgroundDysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer
Singh, V., Yeoh, B. S., Chassaing, B., Xiao, X., Saha, P., Aguilera Olvera, R., Lapek, J. D., Zhang, L., Wang, W.-B., Hao, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.004 · Cited by 532 · cited 1× · see citing works
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One-carbon metabolism in 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].”
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 483 · cited 1× · see citing works
“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.”
BackgroundLoo, T. M., Kamachi, F., Watanabe, Y., Yoshimoto, S., Kanda, H., Arai, Y., Nakajima-Takagi, Y., Iwama, A., Koga, T., Sugimoto, Y., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0932 · Cited by 478 · cited 1× · see citing works
“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
BackgroundCD8+ T cells in the cancer-immunity cycle
Giles, J. R., Globig, A.-M., Kaech, S. M., & Wherry, E. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.005 · Cited by 473 · cited 1× · see citing works
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“Ex vivo studies showed that gut bacteria convert dietary fiber into short-chain fatty acids in MASLD-HCC, leading to an immunosuppressive TME with an elevated CD4 + Treg cell/ CD8 + T-cell ratio [208].”
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“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 415 · cited 2× · see citing works
“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].”
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× · see citing works
“High levels of GLUT1 expression are also associated with poor prognosis in both HCC and iCCA [80–84].”
BackgroundGut microbiome in HCC – Mechanisms, diagnosis and therapy
Schwabe, R. F., & Greten, T. F. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.016 · Cited by 370 · cited 3× · see citing works
“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].”
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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× · see citing works
“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 333 · see citing works
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 317 · cited 1× · see citing works
“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].”
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× · see citing works
“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].”
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 311 · cited 1× · see citing works
“High-cholesterol diets induce HCC in mice, partly through dysregulation of metabolism and calcium signaling [55–57].”
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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].”
BackgroundNAD+ 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 301 · cited 1× · see citing works
“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].”
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 299 · cited 1× · see citing works
“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].”
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 292 · cited 1× · see citing works
“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-citationHalford, 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 291 · see citing works
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“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 280 · see citing works
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“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.”
BackgroundAltorki, 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 273 · cited 1× · see citing works
“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].”
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Gut 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 263 · cited 2× · see citing works
“This induces TLR4-dependent CXCL1 expression in hepatocytes, leading to the recruitment of CXCR2 + PMN-MDSC, and ultimately promoting an immunosuppressive TME [203].”
BackgroundAntagonistic 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 252 · cited 1× · see citing works
“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
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Metabolic 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 241 · cited 5× · see citing works
“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].”
BackgroundDietary supplements and disease prevention — a global overview
Rautiainen, S., Manson, J., Lichtenstein, A., & Sesso, H. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.54 · Cited by 233 · cited 1× · see citing works
“People often consume dietary supplements for health benifits [230].”
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 226 · cited 1× · see citing works
“This leads to an immunosuppressive TME through PGE2 production in obesity-associated HCC mouse models [198, 224], potentially causing ICB resistance [225, 226].”
BackgroundSchneider, K. M., Mohs, A., Gui, W., Galvez, E. J. C., Candels, L. S., Hoenicke, L., Muthukumarasamy, U., Holland, C. H., Elfers, C., Kilic, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31312-5 · Cited by 225 · cited 1× · see citing works
“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 · see citing works
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Lee, 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× · see citing works
“Lee et al. suggested that Lachnoclostridium , along with ursodeoxycholic and ursocholic acids, produce better responses to ICB treatment in patients with unresectable HCC [229].”
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 213 · cited 1× · see citing works
“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].”
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 210 · cited 2× · see citing works
“…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× · see citing works
“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].”
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 209 · cited 1× · see citing works
“PGE2, a bioactive lipid generated from arachidonic acid, has recently been implicated in immune evasion through multiple mechanisms [145].”
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 209 · cited 1× · see citing works
“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].”
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 207 · cited 1× · see citing works
“Thus, combining acetate supplementation with PD-1 blockades significantly boosts anti-tumor immunity [227].”
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 196 · cited 1× · see citing works
“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].”
BackgroundIron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis
Handa, P., Thomas, S., Morgan-Stevenson, V., Maliken, B., Gochanour, E., Boukhar, S., Yeh, M. M., & Kowdley, K. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.3a0318-108r · Cited by 190 · cited 1× · see citing works
“Compared to M1φ, M2φ tends to polarize under low ferrous iron levels [132].”
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 189 · cited 1× · see citing works
“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].”
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× · see citing works
“…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 177 · cited 1× · see citing works
“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× · see citing works
“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 173 · cited 1× · see citing works
“Glutamine, the most abundant amino acid in human blood, is a key carbon source for de novo lipogenesis in mitochondrial dysfunctional HCC [64].”
BackgroundChen, 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× · see citing works
“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].”
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Britten, C. D., Garrett-Mayer, E. S., Chin, S. H., Shirai, K., Öğretmen, B., Bentz, T. A., Brisendine, A., Anderton, K., Cusack, S., Maines, L. W., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2363 · Cited by 168 · see citing works
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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].”
BackgroundDeng, H.-J., Kan, A., Lyu, N., He, M., Huang, X., Qiao, S., Li, S.-L., Lu, W.-H., Xie, Q., Chen, H., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002305 · Cited by 165 · cited 1× · see citing works
“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].”
BackgroundFang, Y., Liu, W.-R., Tang, Z., Ji, X.-D., Zhou, Y., Song, S.-S., Tian, M.-X., Tao, C., Huang, R., Zhu, G., et al. (2022) · Hepatology · doi:10.1002/hep.32348 · Cited by 164 · see citing works
Hypoxia‐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× · see citing works
“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].”
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 157 · cited 1× · see citing works
“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× · see citing works
“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× · see citing works
“Thus, combining GCN2 inhibition with senolytic agents could be an effective treatment strategy in arginine-deprived HCC cells [62].”
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 152 · cited 1× · see citing works
“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].”
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 · see citing works
McDonald, 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 148 · cited 1× · see citing works
“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].”
BackgroundWabitsch, 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 144 · cited 1× · see citing works
“This impairment diminishes the efficacy of ICB therapy, which could be salvaged by metformin [182].”
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., Evan, G., et al. (2020) · Hepatology · doi:10.1002/hep.31391 · Cited by 142 · cited 1× · see citing works
“High-cholesterol diets induce HCC in mice, partly through dysregulation of metabolism and calcium signaling [55–57].”
BackgroundMurai, 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× · see citing works
“Multi-omics study showed lipid accumulation in HCC elevates PD-L1 expression, inducing an immunosuppressive TME [28].”
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 141 · cited 1× · see citing works
“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 141 · cited 1× · see citing works
“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-citationLiu, 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 139 · cited 1× · see citing works
“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
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“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 · see citing works
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× · see citing works
“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.”
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 133 · cited 1× · see citing works
“It has been demonstrated that liver cancer cells typically utilize glycolysis under hypoxic conditions to produce lactate via lactic dehydrogenase (LDH) [38].”
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× · see citing works
“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 129 · cited 1× · see citing works
“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 124 · see citing works
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Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma
Nwosu, Z., Megger, D. A., Hammad, S., Sitek, B., Roessler, S., Ebert, M., Meyer, C., & Dooley, S. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.05.004 · Cited by 122 · cited 3× · see citing works
“Moreover, numerous studies indicate enhanced amino acid metabolism in liver tumors compared to non-tumor tissues [1, 31, 37, 60, 61].”
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× · see citing works
“…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].”
BackgroundLercher, 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 120 · cited 1× · see citing works
“…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].”
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 120 · see citing works
Phoomak, C., Vaeteewoottacharn, K., Silsirivanit, A., Saengboonmee, C., Seubwai, W., Sawanyawisuth, K., Wongkham, C., & Wongkham, S. (2017) · Scientific Reports · doi:10.1038/srep43842 · Cited by 120 · cited 1× · see citing works
“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.”
BackgroundExploring 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 115 · cited 1× · see citing works
“With the advent of immunome-tabolism in cancer treatment [18–22], greater attention should be given to the interplay of metabolism-related immune signaling.”
BackgroundLi, B., Li, Y., Zhou, H., Xu, Y., Cao, Y., Cheng, C., Peng, J., Li, H., Zhang, L., Su, K., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000553 · Cited by 110 · cited 1× · see citing works
“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× · see citing works
“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× · see citing works
“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].”
BackgroundTap, W., Villalobos, V., Cote, G., Burris, H., Janku, F., Mir, O., Beeram, M., Wagner, A., Jiang, L.-W., Wu, B., et al. (2020) · Reactions weekly · doi:10.1007/s40278-020-83841-5 · Cited by 103
SLC2A2 (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 103 · see citing works
Che, Y., Chen, G., Guo, Q., Duan, Y., Feng, H., & Xia, Q. (2023) · Hepatology · doi:10.1097/hep.0000000000000047 · Cited by 100 · cited 1× · see citing works
“Butyrate accumulation disrupts intracellular calcium homeostasis and induces the production of ROS, thus improving the efficacy of TKI therapy in HCC mouse models [202].”
BackgroundJouve, 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 · see citing works
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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× · see citing works
“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 · see citing works
G6PD: A hub for metabolic reprogramming and redox signaling in cancer
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Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis.
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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].”
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× · see citing works
“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.”
BackgroundNelson, M. E., Lahiri, S., Chow, J. D. Y., Byrne, F., Hargett, S., Breen, D. S., Olzomer, E. M., Wu, L. E., Cooney, G., Turner, N., et al. (2017) · Nature Communications · doi:10.1038/ncomms14689 · Cited by 86 · cited 1× · see citing works
“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].”
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× · see citing works
“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× · see citing works
“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× · see citing works
“This results in an immunosuppressive TME dominated by excessive neutrophil infiltration and contributes to poor prognosis in iCCA [147].”
BackgroundSelf-citationMolenaar, R. J., Coelen, R. J. S., Khurshed, M., Roos, E., Caan, M. W. A., Linde, M. E. V., Kouwenhoven, M. C. M., Bramer, J. A. M., Bovée, J. V. M. G., Mathôt, R. A. A., et al. (2017) · BMJ Open · doi:10.1136/bmjopen-2016-014961 · Cited by 82 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“In HCC cells, glycine-derived 1C units support purine and pyrimidine biosynthesis and tumor progression through glycine cleavage system (GCS) flux [73].”
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× · see citing works
“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].”
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 66 · cited 1× · see citing works
“Increasing evidence suggests that the gut microbiota modulates immune responses in the TME of PLC [5, 194, 203, 207, 208].”
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× · see citing works
“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× · see citing works
“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].”
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 62 · cited 1× · see citing works
“This production promotes epithelial-mesenchymal transition (EMT) and HCC metastasis [187].”
BackgroundPlummer, R., Halford, S., Jones, P. S., Wedge, S., Hirschberg, S., Veal, G., Payne, G., Chénard-Poirier, M., Keun, H., & Banerji, U. (2017) · doi:10.1200/jco.2017.35.15_suppl.2516 · Cited by 61 · 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…”
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 · see citing works
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× · see citing works
“…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.-P., Xu, R., Zhang, G.-C., Liu, Z.-Y., Abuduwaili, W., Wang, F., Yu, X.-N., Shi, X., Song, G.-Q., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-03034-7 · Cited by 59 · cited 1× · see citing works
“This iron competition culminates in an M2-like TAM polarization in vitro [133].”
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 55 · cited 1× · see citing works
“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 53 · cited 1× · see citing works
“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].”
BackgroundDecoding complex patterns of genomic rearrangement in hepatocellular carcinoma
Fernandez-Banet, J., Lee, N. P. Y., Chan, K., Gao, H., Liu, X., Sung, W.-K. K., Tan, W., Fan, S. T., Poon, R. T. P., Li, S., et al. (2014) · Genomics · doi:10.1016/j.ygeno.2014.01.003 · Cited by 52 · see citing works
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Cited by
Sorted by citations
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 · see citing works
The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy
Ma, Q., Zhang, W., Wu, K., & Shi, L. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02218-1 · Cited by 88 · see citing works
“Unlike normal cells, cancer cells undergo metabolic reprogramming to meet the increased demands for energy, macromolecule biosynthesis, and redox balance [16, 17].”
Zhang, M.-S., Zheng, H., Jin, H., Zhu, X., Liu, S.-W., Chen, Y., Zhang, H., & Zhang, S. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.09.003 · Cited by 40
“Moreover, interfering glucose metabolic pathways, including OXPHOS, glycolysis and PPP, can also disrupt glucose metabolic process, thus inducing glucose dyshomeo-stasis [28,29].”
Self-citationHuang, Y., Xie, Y., Zhang, Y., Liu, Z., Jiang, W., Ye, Y., Tang, J., Li, Z., Yin, Z., & Lin, X.-J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02370-2 · Cited by 41 · see citing works
“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].”
Fan, S., Wang, W., Che, W., Xu, Y., Jin, C., Dong, L., & Xia, Q. (2025) · Metabolites · doi:10.3390/metabo15030201 · Cited by 43 · see citing works
Wang, L., ChenLiu, Z., Wang, D., & Tang, D. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.140523 · Cited by 28 · see citing works
Liu, J., Zhang, X., Fan, X., Liu, P., Mi, Z., Tan, H., & Rong, P. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03477-6 · Cited by 30 · see citing works
“A hallmark of cancer, including HCC, is metabolic reprogramming [5, 6], in which tumor cells shift their energy production from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect [7].”
Metabolic reprogramming in cancer: signaling pathways and therapeutic targets
Dong, S., & Lei, X. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02582-0 · Cited by 28 · see citing works
Liu, P., Huang, F., Lin, P., Liu, J., Zhou, P., Wang, J., Sun, H., Xing, F., & Ma, H.-Q. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06267-y · Cited by 28 · see citing works
“In recent years, the crosstalk between tumor cell metabolism and the immune microenvironment has garnered increasingly attention for its role in tumorigenesis and progression [16, 37, 38].”
Targeting lipid metabolism via nanomedicine: A prospective strategy for cancer therapy
Huang, X., Hou, S., Li, Y., Xu, G., Xia, N., Duan, Z., Luo, K., & Tian, B. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.123022 · Cited by 23 · see citing works
Recent advances in understanding the immune microenvironment in ovarian cancer
Chen, J., Yang, L., Ma, Y., & Zhang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1412328 · Cited by 18 · see citing works
“The interactions between these components and tumor cells have a signi fi cant impact on tumor progression (19, 20).”
BackgroundNonhistone lactylation: A hub for tumour metabolic reprogramming and epigenetic regulation
Zhang, D., Liang, C., Wu, C., Hawanga, M., Wan, S., Xu, L., Zhang, X., Liu, Y., Hu, F., Wang, M., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06813-8 · Cited by 26 · see citing works
Lin, S.-L., Yang, S.-Y., Tsai, C.-H., Fong, Y., Chen, W.-L., Liu, J.-F., Lin, C.-Y., & Tang, C.-H. (2024) · International Journal on Biological Sciences · doi:10.7150/ijbs.95463 · Cited by 24
“Researchers have established that malignant growth depends on interactions between tumor cells and cells within the tumor microenvironment [7, 8], which is a complex system involving a variety of cell types, including endothelial, fibroblast, and inflammatory cells (e.g., dendritic and macrophage…”
BackgroundBi, Y., Ying, X., Chen, W., Wu, J., Kong, C., Hu, W., Fang, S., Yu, J., Zhai, M., Jiang, C., et al. (2024) · Lipids in Health and Disease · doi:10.1186/s12944-024-02298-4 · Cited by 23 · see citing works
“In HCC and CCA, enhanced anabolic processes and reduced catabolic processes lead to a metabolic imbalance [3, 8].”
BackgroundInsights into the gut-liver axis: mechanisms and emerging therapies in hepatocellular carcinoma
Hu, Y., Gao, M., Chenghuang, J., & Bao, R. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1595853 · Cited by 16 · see citing works
“This leads to HSCs senescence and the senescence-associated secretory phenotype, which secrete in fl ammatory cytokines, chemokines, proteases, and growth factors in the liver, promoting HCC progression (Yoshimoto et al., 2013; Lin et al., 2024).”
Role of cellular senescence in hepatic diseases (Review)
Xing, Y., & Zhu, J. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5623 · Cited by 18 · see citing works
“Second, enhanced aerobic glycolysis sustains Hcc progression by facil‑ itating proliferation, metastasis and chemoresistance (67).”
Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion
Shou, Y., Liu, R., Xiong, H., Xu, K., Chen, X., Huang, L., Zhang, Y., Sheng, H., Zhang, H., & Lü, Y. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02328-3 · Cited by 19 · see citing works
“Arginine is a critical substrate for regulatory T-cells (Tregs) function, and its depletion in the TME—often due to argininosuccinate synthetase 1 (ASS1) downregulation—results in impaired Tregs proliferation and activation, thus weakening the antitumor immune response [1–3].”
Lin, Y., Ruze, R., Zhang, R., Tuergan, T., Wang, M., Tulahong, A., Zhu, D., Yuan, Z., Jiang, T., Aji, T., et al. (2024) · Liver Cancer · doi:10.1159/000542578 · Cited by 17 · see citing works
“This nutrient-rich environment causes alterations in glucose, lipid, and amino acid levels, characteristic of various HCC etiologies [95].”
Mito-Nanozyme: Mitochondria-Targeted Nanozyme for Cancer Therapy
Li, Z., Song, J., Zhao, X., Wang, K., Liang, Y., Zhang, L., Guo, B., & Jiang, W. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.216899 · Cited by 18 · see citing works
RNA m5C methylation in cancer: mechanisms and biological impact
Guan, Z.-Y., Li, W.-D., He, Y.-T., & Guo, W.-Z. (2025) · Oncogenesis · doi:10.1038/s41389-025-00587-w · Cited by 16 · see citing works
Li, C.-H., Yuan, Y.-X., Jiang, X.-L., & Wang, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1702436 · Cited by 15 · see citing works
Lin, Z., Liu, X., Wang, H., Li, S., Miao, Z.-Q., Yang, J., Zhang, Y., Lei, K., Wu, Y.-F., Kang, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61448-z · Cited by 15 · see citing works
“These results implied that AR might play a crucial role in regulating angiogenesis within the AFP − HCC TME.”
InfluentialPan, G.-Q., Yan, Y., Li, R., Chen, X., Zhang, S.-P., Qu, Y., Dong, R., Zhou, Y. J., Zhang, T.-S., Chen, Z.-Q., et al. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156304 · Cited by 15 · see citing works
Oxidative Stress in the Tumor Immune Microenvironment: Mechanisms and Therapeutic Perspectives
Wang, Z., Li, B., Tang, P., Yan, F., Wang, S., Leng, G., Dawa, P., Chen, Y., Guo, Y., Yang, P., et al. (2026) · MedComm – Oncology · doi:10.1002/mog2.70068 · Cited by 15 · see citing works
Chen, Y., Chen, D., Liang, Z., Yu, H., Sun, H., Hu, Y., Jiang, P., Zhang, M., Ye, L., & Li, H. (2025) · Cancer Drug Resistance · doi:10.20517/cdr.2025.120 · Cited by 9 · see citing works
Self-citationNew insights into T cell metabolism in liver cancer: from mechanism to therapy
Xiao, J., Liu, T., Zeng, F., & Zhang, J. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02397-w · Cited by 13 · see citing works
“During the progression of liver cancer, gluconeogenesis, detoxication, bile acid metabolism, and other typical hepatocyte metabolic functions are decreased, and these metabolic changes are accompanied by an increase in tumor progression [20, 21].”
Targeting Txnip-mediated metabolic reprogramming has therapeutic potential for osteoarthritis
Cao, X.-K., Yang, X., Zhang, P., Xu, J.-G., Zhao, J., & Yang, E.-Z. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02394-z · Cited by 14
Single-molecular theranostic metal complexes: Integrating bio-imaging and cancer therapy
Man, X., Zhang, Z., Liang, H., & Yang, F. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.217356 · Cited by 13 · see citing works
Multifaceted roles of lactate dehydrogenase in liver cancer (Review)
Jin, H., Liu, Q., Li, J., Zhao, S.-Y., & Tuo, B. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5756 · Cited by 13 · see citing works
“For example, lactate can enter mitochondria through the lactate shuttle and be converted to pyruvate through reverse catalysis by LDH, which participates in the TCA and provides addi‑ tional energy to cells (65).”
Adapa, S. R., Porshe, S., Talada, D. P., Nywening, T. M., Anderson, M. L., Shaw, T. I., & Jiang, R. H. Y. (2025) · Cancers · doi:10.3390/cancers17193210 · Cited by 12 · see citing works
“These findings supports the concept that tumors can systemically prime distant sites for colonization [72].”
Lactate and lactylation in breast cancer: current understanding and therapeutic opportunities
Huang, L. J., Chen, X., Yan, M., Xiang, Z., & Wu, J. (2025) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2025.0173 · Cited by 5 · see citing works
Metabolic reprogramming: The driving force behind cancer drug resistance
El-Sehrawy, A. A. M. A., Hsu, C.-Y., Alkhathami, A. G., Chandra, M., Basunduwah, T. S., Malathi, H., Senapati, J. N., Gautam, A., Kadhem, M., & Yasin, H. A. (2025) · Seminars in Oncology · doi:10.1016/j.seminoncol.2025.152392 · Cited by 11 · see citing works
Harnessing Next‐Generation 3D Cancer Models to Elucidate Tumor‐Microbiome Crosstalk
Buzhor, M. G., Longobardi, G., Kandli, O., Krinsky, A., Avramoff, O., Katyal, A., Salomon, K., Miari, A., Venkert, D., Barnatan, T. T., et al. (2025) · Advanced Healthcare Materials · doi:10.1002/adhm.202503198 · Cited by 7 · see citing works
Gene regulatory network integration with multi-omics data enhances survival predictions in cancer
Pop, R. T., Hsieh, P., Belova, T., Mathelier, A., & Kuijjer, M. L. (2025) · Briefings in Bioinformatics · doi:10.1093/bib/bbaf315 · Cited by 10 · see citing works
“Lipid metabolism disruptions have been well documented in liver tumours (reviewed in [29, 30]).”
Xue, J., Zhang, L., Zhang, K., Wu, Y., Zhou, K., & Lü, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1697056 · Cited by 9 · see citing works
The Immune Microenvironment in Liver Cancer: From Analysis to Targeting
Lan, J., Li, H., Xue, J., Duan, Y., Sun, J., & Niu, M. (2025) · Advanced Science · doi:10.1002/advs.202518487 · Cited by 10 · see citing works
Hypoxia-mediated m6A modulation in hepatocellular carcinoma: a comprehensive review
Jiang, H., Qian, S.-Y., Pan, D., Jin, C., & Pu, Q.-H. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07155-1 · Cited by 10 · see citing works
Research progress and therapeutic strategies in hepatocellular carcinoma metabolic reprogramming
Wang, H., Lun, Y., Xu, D., Jiang, H., Yan, Y., & Yang, X. H. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.08.023 · Cited by 7 · see citing works
“For example, HCC cells frequently favor glycolysis over oxidative phosphorylation (OXPHOS), even in the presence of oxygen, a phenomenon termed the ‘‘Warburg effect” [16,17], culminating in the generation of substantial lactate to support their rapid growth [18–20].”
Shen, X., Shi, H., Liu, L., Chong, S., Han, J.-W., & Gu, Y.-P. (2025) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-025-05319-9 · Cited by 10
“Metabolic reprogramming represents a hallmark of cancer that enables tumor cells to sustain rapid proliferation, invasion, and survival under nutrient-deprived conditions [7].”
Tian, L., Li, X., Guo, L., Huang, L., Wu, X., & Gao, W. (2024) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2024.216027 · Cited by 16 · see citing works
Li, K., Wang, H., Li, C., Xiao, M., Luo, Y., Shen, S., Li, G., Fu, Y., Chen, W., Shao, R., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-08877-0 · Cited by 9 · see citing works
“In recent years, numerous studies have shown that metabolic reprogramming plays a pivotal role in the growth and spread of cancer cells 2 – 5 .”
Hepatic Fibrosis and Liver Cancer
Anton, A., Friedman, S. L., & Cogliati, B. (2025) · Seminars in Liver Disease · doi:10.1055/a-2779-4937 · Cited by 8 · see citing works
“Aberrant neovessels also modulate immune cell recruitment to hinder effective traf cking of cytotoxic lymphocytes while promoting the in ltration of immunosuppressive cells.”
Lymph node targeting nanomedicines for tumor immunotherapy
Li, X., Cheng, R., Junyi, D., Wu, Y., Ou, L., Yan, T., Zhou, X., Liu, Z., Feng, S., Chen, L., et al. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123735 · Cited by 10 · see citing works
Li, W., Li, G., Luo, C.-S., Yu, Q., & Cui, M. (2025) · Cancer Management and Research · doi:10.2147/cmar.s537930 · Cited by 11 · see citing works
“119,120 Loss of the metabolic regulator Sirt5 is associated with abnormally elevated bile acids, which promote M2-TAM polarization and favour an immunosuppressive TME.”
Liu, W., Fan, B., Fang, T., Li, H., Zhang, J., Liu, B., & Liu, Z. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.08.010 · Cited by 10 · see citing works
“Tumor cells also often exhibit a similar secretory phenotype, secreting cytokines and growth factors such as VEGF, IL-6, and secreted transforming growth factor-beta (TGF-ß ), which contribute to tumor growth, metastasis, and immune evasion 113 .”
Lai, S.-Y., Zhu, X., Sun, W.-D., Bi, S.-Z., Zhang, C.-Y., Liu, A., & Li, J.-H. (2025) · Biomolecules · doi:10.3390/biom15050719 · Cited by 10 · see citing works
“While normal cells predominantly rely on oxidative phosphorylation (OXPHOS) for energy production, cancer cells often prefer glycolysis as their primary energy source, even when ample oxygen is available, a metabolic adaptation referred to as the “Warburg effect” (Figure 2) [45].”
Guo, Z., Yao, Z., Huang, B., Wu, D., Li, Y., Chen, X., Lu, Y., Wang, L., & Lv, W. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112821 · Cited by 9 · see citing works
Hao, Y., Zhang, Y.-N., Zhang, Y., Yang, D., Ren, D., Yue, Y., Li, Q., Fan, Q., Sun, C., Cui, M., et al. (2025) · European Journal of Medical Research · doi:10.1186/s40001-025-03383-9 · Cited by 8 · see citing works
“Over the past decade, immunotherapy has emerged as a major focus in anti-tumour treatment [2].”
Self-citationThe impact of metabolic reprogramming in hepatocellular carcinoma on T cell
Liao, D., An, X., Huang, G., & Yuan, T.-L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1696113 · Cited by 8 · see citing works
“The core of these strategies lies in effectively plundering core resources such as glucose and amino acids from the TME by upregulating the expression of key nutrient transporters on the cell membrane (217, 219).”
Metabolic reprogramming in Helicobacter pylori infection: from mechanisms to therapeutics
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- 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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