Metabolic Regulation of Immune Responses: Molecular Mechanisms, Diseases, and Therapeutic Targets

Abstract

Cancer-associated metabolic reprogramming profoundly reshapes the tumor microenvironment (TME), emerging as a central driver of immune evasion and therapeutic resistance. Increasing evidence indicates that metabolic enzymes function not only as bioenergetic regulators but also as active modulators of immune signaling, immune cell fate, and immune checkpoint expression. To elucidate these complex immunometabolic networks, this review utilizes fructose-1,6-bisphosphatase 1 (FBP1)—a key gluconeogenic enzyme—as a paradigmatic metabolic gatekeeper to illustrate how metabolic dysregulation drives tumor progression. By examining both the canonical metabolic effects and noncanonical signaling mechanisms of such enzymes, we synthesize recent advances demonstrating how metabolic rewiring promotes glycolytic reprogramming, immune suppression, and resistance to immunotherapy. Specifically, we explore broad mechanisms of immune evasion, including STAT3–PD-L1 regulation, modulation of innate immune surveillance, T cell exhaustion, and remodeling of stromal and fibrotic tumor niches. Furthermore, we discuss emerging therapeutic strategies targeting these immunometabolic pathways, encompassing small-molecule modulators, vitamin- and gene-based interventions, nanotechnology-enabled delivery systems, and metabolism-informed combination immunotherapy. Finally, we highlight key challenges, including metabolic heterogeneity and context-dependent enzyme function, emphasizing the need for biomarker-guided precision strategies to translate fundamental immunometabolic insights into durable and safe cancer therapies.

Keywords

immunometabolism / tumor microenvironment / FBP1 / cancer immunotherapy

References

[1] B. Li, B. Qiu, D. S. M. Lee, et al., “Fructose-1,6-bisphosphatase Opposes Renal Carcinoma Progression,” Nature 513, no. 7517 (2014): 251–255.

[2] R. Phillips, “Kidney Cancer: FBP1 Depletion Feeds ccRCC,” Nature Reviews Urology 11, no. 9 (2014): 482.

[3] J. Yang, C. Wang, F. Zhao, et al., “Loss of FBP1 Facilitates Aggressive Features of Hepatocellular Carcinoma Cells Through the Warburg Effect,” Carcinogenesis 38, no. 2 (2016): 134–143.

[4] H. Hirata, K. Sugimachi, H. Komatsu, et al., “Decreased Expression of Fructose-1,6-Bisphosphatase Associates With Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma,” Cancer Research 76, no. 11 (2016): 3265–3276.

[5] B. Wang, Y. Zhou, J. Zhang, et al., “Fructose-1,6-bisphosphatase Loss Modulates STAT3-Dependent Expression of PD-L1 and Cancer Immunity,” Theranostics 10, no. 3 (2020): 1033–1045.

[6] C. Song, J. Zhang, X. Liu, et al., “PTEN Loss Promotes Warburg Effect and Prostate Cancer Cell Growth by Inducing FBP1 Degradation,” Frontiers in Oncology 12 (2022): 911466.

[7] Z. Wang, M. Li, H. Jiang, et al., “Fructose-1,6-Bisphosphatase 1 Functions as a Protein Phosphatase to Dephosphorylate Histone H3 and Suppresses PPARα-Regulated Gene Transcription and Tumour Growth,” Nature Cell Biology 24, no. 11 (2022): 1655–1665.

[8] X. Hu, J. Wang, M. Chu, et al., “Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy,” Molecular Therapy 29, no. 3 (2021): 908–919.

[9] H. Sun, H. Zhang, L. Jing, et al., “FBP1 Is a Potential Prognostic Biomarker and Correlated With Tumor Immunosuppressive Microenvironment in Glioblastoma,” Neurosurgical Review 46, no. 1 (2023): 187.

[10] K. Cheng, N. Cai, X. Yang, et al., “Short-Term Starvation Boosts Anti-PD-L1 Therapy by Reshaping Tumor-Associated Macrophages in Hepatocellular Carcinoma,” Hepatology (2025): 1414–1431.

[11] X. Lyu, P. Wang, Q. Qiao, et al., “Genomic Stratification Based on Microenvironment Immune Types and PD-L1 for Tailoring Therapeutic Strategies in Bladder Cancer,” BMC Cancer 21, no. 1 (2021): 646.

[12] L. L. Bu, G. T. Yu, L. Wu, et al., “STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC,” Journal of Dental Research 96, no. 9 (2017): 1027–1034.

[13] X. Zhang, Y. Zeng, Q. Qu, et al., “PD-L1 Induced by IFN-γ From Tumor-Associated Macrophages via the JAK/STAT3 and PI3K/AKT Signaling Pathways Promoted Progression of Lung Cancer,” International Journal of Clinical Oncology 22, no. 6 (2017): 1026–1033.

[14] Y. Ishida, Y. Agata, K. Shibahara, et al., “Induced Expression of PD-1, a Novel Member of the Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,” The EMBO Journal 11, no. 11 (1992): 3887–3895.

[15] H. Dong, S. E. Strome, D. R. Salomao, et al., “Tumor-Associated B7-H1 Promotes T-Cell Apoptosis: A Potential Mechanism of Immune Evasion,” Nature Medicine 8, no. 8 (2002): 793–800.

[16] H. Dong, G. Zhu, K. Tamada, et al., “B7-H1, a Third Member of the B7 Family, Co-Stimulates T-Cell Proliferation and Interleukin-10 Secretion,” Nature Medicine 5, no. 12 (1999): 1365–1369.

[17] G. J. Freeman, A. J. Long, Y. Iwai, et al., “Engagement of the PD-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation,” The Journal of Experimental Medicine 192, no. 7 (2000): 1027–1034.

[18] K. C. Ohaegbulam, A. Assal, E. Lazar-Molnar, et al., “Human Cancer Immunotherapy With Antibodies to the PD-1 and PD-L1 Pathway,” Trends in Molecular Medicine 21, no. 1 (2015): 24–33.

[19] C. Lu, C. Ren, T. Yang, et al., “Fructose-1,6-Bisphosphatase 1 Interacts With NF-κB p65 to Regulate Breast Tumorigenesis via PIM2 Induced Phosphorylation,” Theranostics 10, no. 19 (2020): 8606–8618.

[20] D. Luo, Q. Yang, H. Wang, et al., “A Predictive Model for Assessing Prognostic Risks in Gastric Cancer Patients Using Gene Expression and Methylation Data,” BMC Medical Genomics 14, no. 1 (2021): 14.

[21] Y. Dong, S. Huaying, W. Danying, et al., “Significance of Methylation of FBP1 Gene in Non-Small Cell Lung Cancer,” BioMed Research International 2018 (2018): 1–9.

[22] H. Sheng, L. Ying, L. Zheng, et al., “Down Expression of FBP1 Is a Negative Prognostic Factor for Non–Small-Cell Lung Cancer,” Cancer Investigation 33, no. 5 (2015): 197–204.

[23] L. Li, L. Yang, Z. Fan, et al., “Hypoxia-Induced GBE1 Expression Promotes Tumor Progression Through Metabolic Reprogramming in Lung Adenocarcinoma,” Signal Transduction and Targeted Therapy 5 (2020): 54.

[24] N. Wang, C. Zhang, W. Wang, et al., “Long Noncoding RNA DANCR Regulates Proliferation and Migration by Epigenetically Silencing FBP1 in Tumorigenesis of Cholangiocarcinoma,” Cell Death & Disease 10 (2019): 585.

[25] C. Dong, T. Yuan, Y. Wu, et al., “Loss of FBP1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-Like Breast Cancer,” Cancer Cell 23, no. 3 (2013): 316–331.

[26] A. Karpathakis, H. Dibra, C. Pipinikas, et al., “Prognostic Impact of Novel Molecular Subtypes of Small Intestinal Neuroendocrine Tumor,” Clinical Cancer Research 22, no. 1 (2016): 250–258.

[27] M. Chen, J. Zhang, N. Li, et al., “Promoter Hypermethylation Mediated Downregulation of FBP1 in Human Hepatocellular Carcinoma and Colon Cancer,” PLoS ONE 6, no. 10 (2011): e25564.

[28] M. Bárcena-Varela, S. Caruso, S. Llerena, et al., “Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma,” Hepatology (Baltimore, Md) 69, no. 2 (2019): 587–603.

[29] L. Li, Y. Yu, Z. Zhang, et al., “TRIM47 Accelerates Aerobic Glycolysis and Tumor Progression Through Regulating Ubiquitination of FBP1 in Pancreatic Cancer,” Pharmacological Research 166 (2021): 105429.

[30] L. Chen, R. Yuan, C. Wen, et al., “E3 Ubiquitin Ligase UBR5 Promotes Pancreatic Cancer Growth and Aerobic Glycolysis by Downregulating FBP1 via Destabilization of C/EBPα,” Oncogene 40, no. 2 (2021): 262–276.

[31] C. Yang, S. Zhu, H. Yang, et al., “USP44 Suppresses Pancreatic Cancer Progression and Overcomes Gemcitabine Resistance by Deubiquitinating FBP1,” American Journal of Cancer Research 9, no. 8 (2019): 1722–1733.

[32] X. Jin, Y. Pan, L. Wang, et al., “MAGE-TRIM28 Complex Promotes the Warburg Effect and Hepatocellular Carcinoma Progression by Targeting FBP1 for Degradation,” Oncogenesis 6, no. 4 (2017): e312.

[33] B. S. Atanassov and S. Y. R. Dent, “USP22 Regulates Cell Proliferation by Deubiquitinating the Transcriptional Regulator FBP1,” EMBO reports 12, no. 9 (2011): 924–930.

[34] B. Zhang, D. Li, X. Jin, et al., “The CDK4/6 Inhibitor PD0332991 Stabilizes FBP1 by Repressing MAGED1 Expression in Pancreatic Ductal Adenocarcinoma,” The International Journal of Biochemistry & Cell Biology 128 (2020): 105859.

[35] L. Gu, Y. Zhu, S. P. Nandi, et al., “FBP1 Controls Liver Cancer Evolution From Senescent MASH Hepatocytes,” Nature 637 (2025): 461–469.

[36] L. N. Yang, Z. Y. Ning, L. Wang, et al., “HSF2 regulates Aerobic Glycolysis by Suppression of FBP1 in Hepatocellular Carcinoma,” American Journal of Cancer Research 9, no. 8 (2019): 1607–1621.

[37] Z. Fan, W. Zheng, H. Li, et al., “LOXL2 Upregulates Hypoxia-Inducible Factor-1α Signaling Through Snail-FBP1 Axis in Hepatocellular Carcinoma Cells,” Oncology Reports 43, no. 5 (2020): 1641–1649.

[38] I. Sengupta, P. Mondal, A. Sengupta, et al., “Epigenetic Regulation of Fructose-1,6-Bisphosphatase 1 by Host Transcription Factor Speckled 110 kDa During Hepatitis B Virus Infection,” The FEBS Journal 289, no. 21 (2022): 6694–6713.

[39] J. Zou, X. Zhu, D. Xiang, et al., “LIX1-Like Protein Promotes Liver Cancer Progression via miR-21-3p-Mediated Inhibition of Fructose-1,6-bisphosphatase,” Acta Pharmaceutica Sinica B 11, no. 6 (2021): 1578–1591.

[40] D. Zhang, Z. Li, T. Li, et al., “miR-517a Promotes Warburg Effect in HCC by Directly Targeting FBP1,” OncoTargets and Therapy 11 (2018): 8025–8032.

[41] C. T. Law, L. Wei, F. H. C. Tsang, et al., “HELLS Regulates Chromatin Remodeling and Epigenetic Silencing of Multiple Tumor Suppressor Genes in Human Hepatocellular Carcinoma,” Hepatology (Baltimore, MD) 69, no. 5 (2019): 2013–2030.

[42] J. Yang, X. Jin, Y. Yan, et al., “Inhibiting Histone Deacetylases Suppresses Glucose Metabolism and Hepatocellular Carcinoma Growth by Restoring FBP1 Expression,” Scientific Reports 7 (2017): 43864.

[43] Z. Liu, Y. You, Q. Chen, et al., “Extracellular Vesicle-Mediated Communication Between Hepatocytes and Natural Killer Cells Promotes Hepatocellular Tumorigenesis,” Molecular Therapy 30, no. 2 (2022): 606–620.

[44] Y. Li, Y. Fu, Y. Zhang, et al., “Nuclear Fructose-1,6-Bisphosphate Inhibits Tumor Growth and Sensitizes Chemotherapy by Targeting HMGB1,” Advanced Science 10, no. 7 (2023): e2203528.

[45] G. M. Liu, Q. Li, P. F. Zhang, et al., “Restoration of FBP1 Suppressed Snail-Induced Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma,” Cell Death & Disease 9 (2018): 1132.

[46] F. Li, P. Huangyang, M. Burrows, et al., “FBP1 loss Disrupts Liver Metabolism and Promotes Tumorigenesis Through a Hepatic Stellate Cell Senescence Secretome,” Nature Cell Biology 22, no. 6 (2020): 728–739.

[47] L. Yan, H. Sun, Y. Chen, et al., “FOXP2 Suppresses the Proliferation, Invasion, and Aerobic Glycolysis of Hepatocellular Carcinoma Cells by Regulating the KDM5A/FBP1 Axis,” Environmental Toxicology 39, no. 1 (2024): 341–356.

[48] S. Wattanavanitchakorn, P. Rojvirat, T. Chavalit, et al., “CCAAT-Enhancer Binding Protein-α (C/EBPα) and Hepatocyte Nuclear Factor 4α (HNF4α) Regulate Expression of the Human Fructose-1,6-Bisphosphatase 1 (FBP1) Gene in human Hepatocellular Carcinoma HepG2 Cells,” PLoS ONE 13, no. 3 (2018): e0194252.

[49] C. H. Li, M. H. Chan, and Y. C. Chang, “The Role of Fructose 1,6-Bisphosphate-Mediated Glycolysis/Gluconeogenesis Genes in Cancer Prognosis,” Aging 14, no. 7 (2022): 3233–3258.

[50] Q. Guo, K. Li, N. Jiang, et al., “A Novel Risk Model of Three Gefitinib-Related Genes FBP1, SBK1 and AURKA Is Related to the Immune Microenvironment and Is Predicting Prognosis of Lung Adenocarcinoma Patients,” Aging 15, no. 18 (2023): 9633–9660.

[51] T. Mu, H. Li, and X. Li, “Prognostic Implication of Energy Metabolism-Related Gene Signatures in Lung Adenocarcinoma,” Frontiers in Oncology 12 (2022): 867470.

[52] Z. Dai, T. Liu, G. Liu, et al., “Identification of Clinical and Tumor Microenvironment Characteristics of Hypoxia-Related Risk Signature in Lung Adenocarcinoma,” Frontiers in Molecular Biosciences 8 (2021): 757421.

[53] C. Zhang, B. Tang, J. Hu, et al., “Neutrophils Correlate With Hypoxia Microenvironment and Promote Progression of Non-Small-Cell Lung Cancer,” Bioengineered 12, no. 1 (2021): 8872–8884.

[54] Y. Dong, S. Huaying, W. Danying, et al., “Significance of Methylation of FBP1 Gene in Non-Small Cell Lung Cancer,” BioMed Research International 2018 (2018): 3726091.

[55] J. Zhang, J. Wang, H. Xing, et al., “Down-Regulation of FBP1 by ZEB1-Mediated Repression Confers to Growth and Invasion in Lung Cancer Cells,” Molecular and Cellular Biochemistry 411, no. 1–2 (2016): 331–340.

[56] Q. Dai, N. Li, and X. Zhou, “Increased miR-21a Provides Metabolic Advantages Through Suppression of FBP1 Expression in Non-Small Cell Lung Cancer Cells,” American Journal of Cancer Research 7, no. 11 (2017): 2121–2130..

[57] J. Dai, Y. Ji, W. Wang, et al., “Loss of Fructose-1,6-Bisphosphatase Induces Glycolysis and Promotes Apoptosis Resistance of Cancer Stem-Like Cells: An Important Role in Hexavalent Chromium-Induced Carcinogenesis,” Toxicology and Applied Pharmacology 331 (2017): 164–173.

[58] C. Li, L. Zhu, Y. Yang, et al., “Overexpression of FBP1 Enhances Dendritic Cell Activation and Maturation by Inhibiting Glycolysis and Promoting the Secretion of IL33 in Lung Adenocarcinoma,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease 1871, no. 1 (2025): 167559.

[59] T. He, Y. Wang, W. Lv, et al., “FBP1 Inhibits NSCLC Stemness by Promoting Ubiquitination of Notch1 Intracellular Domain and Accelerating Degradation,” Cellular and Molecular Life Sciences 81 (2024): 87.

[60] Z. Chen, W. J. Tang, Y. H. Zhou, et al., “Andrographolide Inhibits Non-Small Cell Lung Cancer Cell Proliferation Through the Activation of the Mitochondrial Apoptosis Pathway and by Reprogramming Host Glucose Metabolism,” Annals of Translational Medicine 9, no. 22 (2021): 1701.

[61] J. Li, P. Dai, J. Sun, et al., “FBP1 Induced by β-Elemene Enhances the Sensitivity of Gefitinib in Lung Cancer,” Thoracic Cancer 14, no. 4 (2023): 371–380.

[62] M. Li, Z. Wang, T. Tao, et al., “Fructose-1,6-Bisphosphatase 1 Dephosphorylates and Inhibits TERT for Tumor Suppression,” Nature Chemical Biology 20, no. 11 (2024): 1505–1513.

[63] L. Shi, C. Zhao, H. Pu, et al., “FBP1 Expression Is Associated With Basal-Like Breast Carcinoma,” Oncology Letters 13, no. 5 (2017): 3046–3056.

[64] C. Luís, F. Schmitt, R. Fernandes, et al., “Breast Cancer Molecular Subtypes Differentially Express Gluconeogenic Rate-Limiting Enzymes-Obesity as a Crucial Player,” Cancers 15, no. 20 (2023): 4936.

[65] E. S. Cho, N. H. Kim, J. S. Yun, et al., “Breast Cancer Subtypes Underlying EMT-Mediated Catabolic Metabolism,” Cells 9, no. 9 (2020): 2064.

[66] H. Harami-Papp, L. S. Pongor, G. Munkácsy, et al., “TP53 Mutation Hits Energy Metabolism and Increases Glycolysis in Breast Cancer,” Oncotarget 7, no. 41 (2016): 67183–67195.

[67] X. Li, E. Vail, H. Maluf, et al., “Gene Expression Profiling of Fibroepithelial Lesions of the Breast,” International Journal of Molecular Sciences 24, no. 10 (2023): 9041.

[68] J. Chen, H. J. Lee, X. Wu, et al., “Gain of Glucose-Independent Growth Upon Metastasis of Breast Cancer Cells to the Brain,” Cancer Research 75, no. 3 (2015): 554–565.

[69] I. Yustisia, R. Amriani, H. Cangara, et al., “High Expression of FBP1 and LDHB in Fibroadenomas and Invasive Breast Cancers,” Breast Disease 40, no. 4 (2021): 251–256.

[70] F. Zhang, B. Liu, Q. Deng, et al., “UCP1 Regulates ALDH-Positive Breast Cancer Stem Cells Through Releasing the Suppression of Snail on FBP1,” Cell Biology and Toxicology 37, no. 2 (2021): 277–291.

[71] K. Li, M. Ying, F. Feng, et al., “Fructose-1,6-bisphosphatase Is a Novel Regulator of Wnt/β-Catenin Pathway in Breast Cancer,” Biomedicine & Pharmacotherapy 84 (2016): 1144–1149.

[72] L. Shi, C. He, Z. Li, et al., “FBP1 Modulates Cell Metabolism of Breast Cancer Cells by Inhibiting the Expression of HIF-1α,” Neoplasma 64, no. 4 (2017): 535–542.

[73] Y. Liu, Y. Jiang, N. Wang, et al., “Invalidation of Mitophagy by FBP1-Mediated Repression Promotes Apoptosis in Breast Cancer,” Tumor Biology 39, no. 6 (2017): 1010428317708779.

[74] X. Peng, L. Ma, X. Chen, et al., “Inhibition of FBP1 Expression by KMT5A Through TWIST1 Methylation Is One of the Mechanisms Leading to Chemoresistance in Breast Cancer,” Oncology Reports 52, no. 2 (2024): 110.

[75] M. Cisneros-Villanueva, M. A. Fonseca-Montaño, M. Ríos-Romero, et al., “LncRNA SOX9-AS1 Triggers a Transcriptional Program Involved in Lipid Metabolic Reprogramming, Cell Migration and Invasion in Triple-Negative Breast Cancer,” Scientific Reports 14, no. 1 (2024): 1483.

[76] D. Fu, J. Li, J. Wei, et al., “HMGB2 is Associated With Malignancy and Regulates Warburg Effect by Targeting LDHB and FBP1 in Breast Cancer,” Cell Communication and Signaling 16, no. 1 (2018): 8.

[77] Y. Li, B. Jiang, L. Zeng, et al., “Adipocyte-Derived Exosomes Promote the Progression of Triple-Negative Breast Cancer Through circCRIM1-Dependent OGA Activation,” Environmental Research 239, no. pt. 1 (2023): 117266.

[78] C. B. Zhao, L. Shi, H. H. Pu, et al., “The Promoting Effect of Radiation on Glucose Metabolism in Breast Cancer Cells Under the Treatment of Cobalt Chloride,” Pathology Oncology Research 23, no. 1 (2017): 47–53.

[79] M. Liu, Q. Pan, R. Xiao, et al., “A Cluster of Metabolism-Related Genes Predict Prognosis and Progression of Clear Cell Renal Cell Carcinoma,” Scientific Reports 10, no. 1 (2020): 12949.

[80] Q. Xing, T. Zeng, S. Liu, et al., “A Novel 10 Glycolysis-Related Genes Signature Could Predict Overall Survival for Clear Cell Renal Cell Carcinoma,” BMC Cancer 21, no. 1 (2021): 381.

[81] Y. Zhang, M. Chen, M. Liu, et al., “Glycolysis-Related Genes Serve as Potential Prognostic Biomarkers in Clear Cell Renal Cell Carcinoma,” Oxidative Medicine and Cellular Longevity 2021 (2021): 6699808.

[82] Z. Li, G. Du, R. Zhao, et al., “Identification and Validation of a Hypoxia-Related Prognostic Signature in Clear Cell Renal Cell Carcinoma Patients,” Medicine 100, no. 39 (2021): e27374.

[83] Z. Sun, W. Tao, X. Guo, et al., “Construction of a Lactate-Related Prognostic Signature for Predicting Prognosis, Tumor Microenvironment, and Immune Response in Kidney Renal Clear Cell Carcinoma,” Frontiers in Immunology 13 (2022): 818984.

[84] X. H. Ning, T. Li, Y. Q. Gong, et al., “Association Between FBP1 and Hypoxia-Related Gene Expression in Clear Cell Renal Cell Carcinoma,” Oncology Letters 11, no. 6 (2016): 4095–4098.

[85] J. C. Van der Mijn, D. J. Panka, A. K. Geissler, et al., “Novel Drugs That Target the Metabolic Reprogramming in Renal Cell Cancer,” Cancer & Metabolism 4 (2016): 14.

[86] D. Ju, Y. Liang, G. Hou, et al., “FBP1 /miR-24-1/Enhancer Axis Activation Blocks Renal Cell Carcinoma Progression via Warburg Effect,” Frontiers in Oncology 12 (2022): 928373.

[87] X. Zhang, S. Li, J. He, et al., “TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling,” Cancer Research 82, no. 11 (2022): 2097–2109.

[88] C. Feng, Y. Li, K. Li, et al., “PFKFB4 is Overexpressed in Clear-Cell Renal Cell Carcinoma Promoting Pentose Phosphate Pathway That Mediates Sunitinib Resistance,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 308.

[89] B. Wang, P. Fan, J. Zhao, et al., “FBP1 loss Contributes to BET Inhibitors Resistance by Undermining c-Myc Expression in Pancreatic Ductal Adenocarcinoma,” Journal of Experimental & Clinical Cancer Research 37, no. 1 (2018): 224.

[90] X. Cheng, B. Zhang, F. Guo, et al., “Deubiquitination of FBP1 by USP7 Blocks FBP1-DNMT1 Interaction and Decreases the Sensitivity of Pancreatic Cancer Cells to PARP Inhibitors,” Molecular Oncology 16, no. 7 (2022): 1591–1607.

[91] L. Y. Chen, C. S. Cheng, C. Qu, et al., “CBX3 promotes Proliferation and Regulates Glycolysis via Suppressing FBP1 in Pancreatic Cancer,” Biochemical and Biophysical Research Communications 500, no. 3 (2018): 691–697.

[92] J. K. Nelson, M. Z. Thin, T. Evan, et al., “USP25 promotes Pathological HIF-1-Driven Metabolic Reprogramming and Is a Potential Therapeutic Target in Pancreatic Cancer,” Nature Communications 13, no. 1 (2022): 2070.

[93] C. Yang, S. Zhu, H. Yang, et al., “FBP1 binds to the Bromodomain of BRD4 to Inhibit Pancreatic Cancer Progression,” American Journal of Cancer Research 10, no. 2 (2020): 523–535.

[94] X. Jin, Y. Pan, L. Wang, et al., “Fructose-1,6-Bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction,” Cancer Research 77, no. 16 (2017): 4328–4341.

[95] Z. Wang and C. Dong, “Gluconeogenesis in Cancer: Function and Regulation of PEPCK, FBPase, and G6Pase,” Trends in Cancer 5, no. 1 (2019): 30–45.

[96] T. Wei and P. F. Lambert, “Role of IQGAP1 in Carcinogenesis,” Cancers 13, no. 16 (2021): 3940.

[97] Y. Zhu, M. Shi, H. Chen, et al., “NPM1 Activates Metabolic Changes by Inhibiting FBP1 While Promoting the Tumorigenicity of Pancreatic Cancer Cells,” Oncotarget 6, no. 25 (2015): 21443–21451.

[98] G. Digiacomo, F. Volta, I. Garajova, R. Balsano, A. Cavazzoni, et al., “Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC,” Life 11, no. 8 (2021): 843.

[99] A. Gizak, B. Budziak, A. Domaradzka, et al., “Fructose 1,6-bisphosphatase as a Promising Target of Anticancer Treatment,” Advances in Biological Regulation 95 (2025): 101057.

[100] A. Tuerhong, J. Xu, S. Shi, et al., “Overcoming Chemoresistance by Targeting Reprogrammed Metabolism: The Achilles' Heel of Pancreatic Ductal Adenocarcinoma,” Cellular and Molecular Life Sciences 78, no. 14 (2021): 5505–5526.

[101] Z. Zhang and H. J. Zhang, “Glycometabolic Rearrangements—Aerobic Glycolysis in Pancreatic Ductal Adenocarcinoma (PDAC): Roles, Regulatory Networks, and Therapeutic Potential,” Expert Opinion on Therapeutic Targets 25, no. 12 (2021): 1077–1093.

[102] X. He, X. Zhong, Y. Fang, et al., “AF9 Sustains Glycolysis in Colorectal Cancer via H3K9ac-Mediated PCK2 and FBP1 Transcription,” Clinical and Translational Medicine 13, no. 8 (2023): e1352.

[103] Z. Pan, J. Cai, J. Lin, et al., “A Novel Protein Encoded by circFNDC3B Inhibits Tumor Progression and EMT Through Regulating Snail in Colon Cancer,” Molecular Cancer 19, no. 1 (2020): 71.

[104] Q. Li, P. Wei, J. Wu, et al., “The FOXC1/FBP1 Signaling Axis Promotes Colorectal Cancer Proliferation by Enhancing the Warburg Effect,” Oncogene 38, no. 4 (2019): 483–496.

[105] W. Zhu, H. Chu, Y. Zhang, et al., “Fructose-1,6-Bisphosphatase 1 Dephosphorylates IκBα and Suppresses Colorectal Tumorigenesis,” Cell Research 33, no. 3 (2023): 245–257.

[106] Z. Chen, H. Bao, J. Long, et al., “GBE1 Promotes Glioma Progression by Enhancing Aerobic Glycolysis Through Inhibition of FBP1,” Cancers 15, no. 5 (2023): 1594.

[107] B. Son, S. Lee, H. Kim, et al., “Decreased FBP1 Expression Rewires Metabolic Processes Affecting Aggressiveness of Glioblastoma,” Oncogene 39, no. 1 (2020): 36–49.

[108] J. Xu, Y. Guo, W. Ning, et al., “Comprehensive Analyses of Glucose Metabolism in Glioma Reveal the Glioma-Promoting Effect of GALM,” Frontiers in Cell and Developmental Biology 9 (2021): 717182.

[109] X. R. Li, K. Q. Zhou, Z. Yin, et al., “Knockdown of FBP1 Enhances Radiosensitivity in Prostate Cancer Cells by Activating Autophagy,” Neoplasma 67, no. 5 (2020): 982–991.

[110] C. Zhao, Z. Liu, J. Peng, et al., “TRIM47 Promotes the Warburg Effect and Reduces Ferroptosis in Prostate Cancer by FBP1 and FOXO1,” Translational Andrology and Urology 13, no. 9 (2024): 1991–2004.

[111] X. Liu, X. Wang, J. Zhang, et al., “Warburg Effect Revisited: An Epigenetic Link Between Glycolysis and Gastric Carcinogenesis,” Oncogene 29, no. 3 (2010): 442–450.

[112] J. Yu, J. Li, Y. Chen, et al., “Snail Enhances Glycolysis in the Epithelial-Mesenchymal Transition Process by Targeting FBP1 in Gastric Cancer,” Cellular Physiology and Biochemistry 43, no. 1 (2017): 31–38.

[113] F. Han, S. Guo, C. Huang, et al., “Gastric Cancer Mesenchymal Stem Cells Inhibit Natural Killer Cell Function by Up-Regulating FBP1,” Central-European Journal of Immunology 46, no. 4 (2021): 427–437.

[114] W. Zhao, J. Zhao, X. Guo, et al., “LncRNA MT1JP Plays a Protective Role in Intrahepatic Cholangiocarcinoma by Regulating miR-18a-5p/FBP1 Axis,” BMC Cancer 21, no. 1 (2021): 142.

[115] W. Zhao, J. Zhao, K. Li, et al., “Oncogenic Role of the NFATC2/NEDD4/FBP1 Axis in Cholangiocarcinoma,” Laboratory Investigation 103, no. 9 (2023): 100193.

[116] W. Zhao, S. Yang, J. Chen, et al., “Forced Overexpression of FBP1 Inhibits Proliferation and Metastasis in Cholangiocarcinoma Cells via Wnt/β-Catenin Pathway,” Life Sciences 210 (2018): 224–234.

[117] D. Bekric, D. Neureiter, C. Ablinger, et al., “Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer,” Cancers 15, no. 5 (2023): 1569.

[118] X. Xiong, J. Zhang, X. Hua, et al., “FBP1 Promotes Ovarian Cancer Development Through the Acceleration of Cell Cycle Transition and Metastasis,” Oncology Letters 16, no. 2 (2018): 1682–1688.

[119] X. Xiong, X. Lai, J. Zhang, et al., “FBP1 Knockdown Decreases Ovarian Cancer Formation and Cisplatin Resistance Through EZH2-Mediated H3K27me3,” Bioscience Reports 42, no. 9 (2022): BSR20221002.

[120] H. Li, Z. Qi, Y. Niu, et al., “FBP1 Regulates Proliferation, Metastasis, and Chemoresistance by Participating in C-MYC/STAT3 Signaling Axis in Ovarian Cancer,” Oncogene 40, no. 40 (2021): 5938–5949.

[121] E. Saulle, I. Spinello, M. T. Quaranta, et al., “Advances in Understanding the Links Between Metabolism and Autophagy in Acute Myeloid Leukemia,” Cells 12, no. 11 (2023): 1553.

[122] Y. Xu, C. Hino, D. J. Baylink, et al., “Vitamin D Activates FBP1 to Block the Warburg Effect and Modulate Blast Metabolism in Acute Myeloid Leukemia,” Biomarker Research 10, no. 1 (2022): 16.

[123] Y. Xu, L. Tran, J. Tang, et al., “FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability Through Activating P53 and Modulating the Mitochondrial Quality Control System in Vitro,” International Journal of Molecular Sciences 23, no. 19 (2022): 11387.

[124] H. Mizuno, J. Koya, Y. Masamoto, et al., “Evi1 Upregulates Fbp1 and Supports Progression of Acute Myeloid Leukemia Through Pentose Phosphate Pathway Activation,” Cancer Science 112, no. 10 (2021): 4112–4126.

[125] V. Nurminen, A. Neme, S. Seuter, et al., “Modulation of Vitamin D Signaling by the Pioneer Factor CEBPA,” Biochimica et Biophysica Acta 1862, no. 1 (2019): 96–106.

[126] A. Damanakis, P. S. Plum, F. Gebauer, et al., “Fructose-1,6-bisphosphatase 1 (FBP1) Is an Independent Biomarker Associated With a Favorable Prognosis in Esophageal Adenocarcinoma,” Journal of Cancer Research and Clinical Oncology 148, no. 9 (2022): 2287–2293.

[127] D. J. Nancarrow, A. D. Clouston, B. M. Smithers, et al., “Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma,” PLoS ONE 6, no. 7 (2011): e22513.

[128] Q. Huai, W. Guo, L. Han, et al., “Identification of Prognostic Genes and Tumor-Infiltrating Immune Cells in the Tumor Microenvironment of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma,” Translational Cancer Research 10, no. 4 (2021): 1787–1803.

[129] Y. He, R. Hua, B. Li, et al., “Loss of FBP1 Promotes Proliferation, Migration, and Invasion by Regulating Fatty Acid Metabolism in Esophageal Squamous Cell Carcinoma,” Aging 13, no. 4 (2020): 4986–4998.

[130] M. Y. Cui, X. Yi, Z. Z. Cao, et al., “Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review,” Journal of Oncology 2022 (2022): 4257359.

[131] M. Stachowiak, M. Szymanski, A. Ornoch, et al., “SWI/SNF Chromatin Remodeling Complex and Glucose Metabolism Are Deregulated in Advanced Bladder Cancer,” Iubmb Life 72, no. 6 (2020): 1175–1188.

[132] J. Ma, Z. Guo, X. Yang, et al., “Exploration of Various Roles of Hypoxia Genes in Osteosarcoma,” Scientific Reports 12, no. 1 (2022): 18293.

[133] T. Ma, C. Peng, D. Wu, et al., “Immune-Based Prognostic Biomarkers Associated With Metastasis of Osteosarcoma,” General Physiology and Biophysics 42, no. 1 (2023): 1–12.

[134] H. Li, M. Li, Y. Pang, et al., “Fructose-1,6-Bisphosphatase-1 Decrease May Promote Carcinogenesis and Chemoresistance in Cervical Cancer,” Molecular Medicine Reports 16, no. 6 (2017): 8563–8571.

[135] V. Chandel, P. P. Sharma, S. A. Nayar, et al., “In Silico Identification of Potential Inhibitor for TP53-Induced Glycolysis and Apoptosis Regulator in Head and Neck Squamous Cell Carcinoma,” 3 Biotech 11, no. 3 (2021): 117.

[136] H. Li, W. Xie, X. Huang, et al., “FBP1 Over-Expression Suppresses HIF-1α in Papillary Thyroid Cancer,” Scientific Reports 14, no. 1 (2024): 29167.

[137] P. Zhang, Y. Shao, F. Quan, et al., “FBP1 Enhances Radiosensitivity by Suppressing Glycolysis via the FBXW7/mTOR Axis in Nasopharyngeal Carcinoma Cells,” Life Sciences 283 (2021): 119840.

[138] S. L. Friedman, F. J. Roll, J. Boyles, et al., “Hepatic Lipocytes: The Principal Collagen-producing Cells of Normal Rat Liver,” Proceedings of the National Academy of Sciences of the United States of America 82 (1985): 8681–8685.

[139] J. J. Maher and R. F. McGuire, “Extracellular Matrix Gene Expression Increases Preferentially in Rat Lipocytes and Sinusoidal Endothelial Cells During Hepatic Fibrosis in Vivo,” The Journal of Clinical Investigation 86 (1990): 1641–1648.

[140] I. Mederacke, C. C. Hsu, J. S. Troeger, et al., “Fate Tracing Reveals Hepatic Stellate Cells as Dominant Contributors to Liver Fibrosis Independent of Its Aetiology,” Nature Communications 4 (2013): 2823.

[141] I. H. Kim, “The Potential Role of Elk-3/Egr-1 Signaling Pathway in the Epithelial-Mesenchymal Transition During Liver Fibrosis,” Gut and Liver 11 (2017): 11–12.

[142] S. Calogero, F. Grassi, A. Aguzzi, et al., “The Lack of Chromosomal Protein Hmg1 Does Not Disrupt Cell Growth but Causes Lethal Hypoglycaemia in Newborn Mice,” Nature Genetics 22 (1999): 276–280.

[143] X. Yang, W. Tang, Y. He, et al., “A Novel Fatty-acid Metabolism-based Classification for Triple Negative Breast Cancer,” Aging 15 (2023): 1177–1198.

[144] S. Affo, L. X. Yu, and R. F. Schwabe, “The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer,” Annual Review of Pathology 12 (2017): 153–186.

[145] S. L. Friedman, “Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver,” Physiological Reviews 88 (2008): 125–172.

[146] P. Li, K. Li, W. Yuan, et al., “1α,25(OH)2D3 ameliorates Insulin Resistance by Alleviating Γδ T Cell Inflammation via Enhancing Fructose-1,6-bisphosphatase 1 Expression,” Theranostics 13 (2023): 5290–5304.

[147] Y. Xu, D. Xia, K. Huang, et al., “Hypoxia-induced P4HA1 Overexpression Promotes Post-Ischemic Angiogenesis by Enhancing Endothelial Glycolysis Through Downregulating FBP1,” Journal of Translational Medicine 22 (2024): 74.

[148] H. Yu, H. Lee, A. Herrmann, et al., “Revisiting STAT3 Signalling in Cancer: New and Unexpected Biological Functions,” Nature Reviews Cancer 14 (2014): 736–746.

[149] A. Jarnicki, T. Putoczki, and M. Ernst, “Stat3: Linking Inflammation to Epithelial Cancer—More Than a “Gut” Feeling?,” Cell Division 5 (2010): 14.

[150] M. B. Lankadasari, J. S. Aparna, S. Mohammed, et al., “Targeting S1PR1/STAT3 Loop Abrogates Desmoplasia and Chemosensitizes Pancreatic Cancer to Gemcitabine,” Theranostics 8 (2018): 3824–3840.

[151] H. Zhu, L. L. Chang, F. J. Yan, et al., “AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer,” Theranostics 8 (2018): 676–692.

[152] S. Grivennikov, E. Karin, J. Terzic, et al., “IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer,” Cancer Cell 15 (2009): 103–113.

[153] J. Bollrath, T. J. Phesse, V. A. Von Burstin, et al., “gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression During Colitis-associated Tumorigenesis,” Cancer Cell 15 (2009): 91–102.

[154] J. Bromberg and T. C. Wang, “Inflammation and Cancer: IL-6 and STAT3 Complete the Link,” Cancer Cell 15 (2009): 79–80.

[155] B. Hu, E. Elinav, S. Huber, et al., “Microbiota-induced Activation of Epithelial IL-6 Signaling Links Inflammasome-Driven Inflammation With Transmissible Cancer,” Proceedings of the National Academy of Sciences of the United States of America 110 (2013): 9862–9867.

[156] P. Fan, J. Ma, and X. Jin, “Far Upstream Element-Binding Protein 1 Is Up-Regulated in Pancreatic Cancer and Modulates Immune Response by Increasing Programmed Death Ligand 1,” Biochemical and Biophysical Research Communications 505 (2018): 830–836.

[157] M. Santarpia, A. Aguilar, I. Chaib, et al., “Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies,” Cancers 12, no. 6 (2020): 1475.

[158] J. Cong, X. Wang, X. Zheng, et al., “Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis During Lung Cancer Progression,” Cell Metabolism 28, no. 2 (2018): e5.

[159] K. De Bock, M. Georgiadou, S. Schoors, et al., “Role of PFKFB3-Driven Glycolysis in Vessel Sprouting,” Cell 154, no. 3 (2013): 651–663.

[160] M. Potente and P. Carmeliet, “The Link Between Angiogenesis and Endothelial Metabolism,” Annual Review of Physiology 79, no. 1 (2017): 43–66.

[161] Z. Yang, M. Yu, X. Li, et al., “Retinoic Acid Inhibits the Angiogenesis of Human Embryonic Stem Cell-Derived Endothelial Cells by Activating FBP1-Mediated Gluconeogenesis,” Stem Cell Research & Therapy 13, no. 1 (2022): 239.

[162] Z. Wang, T. He, W. Lv, et al., “Down-Regulation of FBP1 in Lung Adenocarcinoma Cells Promotes Proliferation and Invasion Through SLUG-Mediated Epithelial Mesenchymal Transformation,” Translational Cancer Research 12, no. 2 (2023): 236–246.

[163] S. W. Nelson, R. B. Honzatko, and H. J. Fromm, “Origin of Cooperativity in the Activation of Fructose-1,6-Bisphosphatase by Mg2+,” Journal of Biological Chemistry 279, no. 18 (2004): 18481–18487.

[164] Y. Xu, K. Payne, L. H. G. Pham, et al., “A Novel Vitamin D Gene Therapy for Acute Myeloid Leukemia,” Translational Oncology 13, no. 12 (2020): 100869.

[165] L. Cong, J. Shi, J. Zhao, et al., “Huaier Inhibits Cholangiocarcinoma Cells Through the Twist1/FBP1/Wnt/β-Catenin Axis,” Molecular Biology Reports 51, no. 1 (2024): 842.

[166] W. Zhu, Y. Zhu, S. Zhang, et al., “1,25-Dihydroxyvitamin D Regulates Macrophage Activation Through FBP1/PKR and Ameliorates Arthritis in TNF-Transgenic Mice,” Journal of Steroid Biochemistry and Molecular Biology 228 (2023): 106251.

[167] K. Fujisawa, K. Umesono, Y. Kikawa, et al., “Identification of a Response Element for Vitamin D3 and Retinoic Acid in the Promoter Region of the Human Fructose-1,6-Bisphosphatase Gene,” Journal of Biochemistry 127, no. 3 (2000): 373–382.

[168] D. H. Solomon, M. C. Raynal, G. A. Tejwani, et al., “Activation of the Fructose 1,6-Bisphosphatase Gene by 1,25-Dihydroxyvitamin D3 During Monocytic Differentiation,” Proceedings of the National Academy of Sciences of the United States of America 85, no. 18 (1988): 6904–6908.

[169] D. J. Shin and M. M. McGrane, “Vitamin A Regulates Genes Involved in Hepatic Gluconeogenesis in Mice: Phosphoenolpyruvate Carboxykinase, Fructose-1,6-Bisphosphatase and 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase,” Journal of Nutrition 127, no. 7 (1997): 1274–1278.

[170] R. J. Chandler, “Messenger RNA Therapy as an Option for Treating Metabolic Disorders,” Proceedings of the National Academy of Sciences of the United States of America 116, no. 42 (2019): 20804–20806.

[171] H. Kim, R. Zenhausern, K. Gentry, et al., “Lipid Nanoparticle-Mediated mRNA Delivery to CD34+ Cells in Rhesus Monkeys,” Nature Biotechnology 43, no. 11 (2024): 1813–1820.

[172] N. C. Bellocq, S. H. Pun, G. S. Jensen, et al., “Transferrin-Containing, Cyclodextrin Polymer-Based Particles for Tumor-Targeted Gene Delivery,” Bioconjugate Chemistry 14, no. 6 (2003): 1122–1132.

[173] Z. Cheng, M. Li, R. Dey, et al., “Nanomaterials for Cancer Therapy: Current Progress and Perspectives,” Journal of Hematology & Oncology 14, no. 1 (2021): 85.

[174] W. Gao, Z. Wang, L. Lv, et al., “Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues,” Theranostics 6, no. 8 (2016): 1131–1144.

[175] A. Sahu, K. Min, J. Jeon, et al., “Catalytic Nanographene Oxide With Hemin for Enhanced Photodynamic Therapy,” Journal of Controlled Release 326 (2020): 442–454.

[176] X. Zhang, Y. Zheng, Z. Wang, et al., “Methotrexate-Loaded PLGA Nanobubbles for Ultrasound Imaging and Synergistic Targeted Therapy of Residual Tumor During HIFU Ablation,” Biomaterials 35, no. 19 (2014): 5148–5161.

[177] S. Martín-Saldaña, R. Palao-Suay, M. R. Aguilar, et al., “Polymeric Nanoparticles Loaded With Dexamethasone or α-Tocopheryl Succinate to Prevent Cisplatin-Induced Ototoxicity,” Acta Biomaterialia 53 (2017): 199–210.

[178] M. S. Kim, M. J. Haney, Y. Zhao, et al., “Engineering Macrophage-Derived Exosomes for Targeted Paclitaxel Delivery to Pulmonary Metastases: In Vitro and in Vivo Evaluations,” Nanomedicine: Nanotechnology, Biology, and Medicine 14, no. 1 (2018): 195–204.

[179] H. Wei, J. Chen, S. Wang, et al., “A Nanodrug Consisting of Doxorubicin and Exosome Derived From Mesenchymal Stem Cells for Osteosarcoma Treatment in Vitro,” International Journal of Nanomedicine 14 (2019): 8603–8610.

[180] L. Meng, X. Xia, Y. Yang, et al., “Co-Encapsulation of Paclitaxel and Baicalein in Nanoemulsions to Overcome Multidrug Resistance via Oxidative Stress Augmentation and P-Glycoprotein Inhibition,” International Journal of Pharmaceutics 513, no. 1 (2016): 8–16.

[181] N. Maghsoudnia, R. Baradaran Eftekhari, A. Naderi Sohi, et al., “Mitochondrial Delivery of MicroRNA Mimic Let-7b to NSCLC Cells by PAMAM-Based Nanoparticles,” Journal of Drug Targeting 28, no. 7 (2020): 818–830.

[182] K. Jeong, Y. J. Yu, J. Y. You, et al., “Exosome-Mediated microRNA-497 Delivery for Anti-Cancer Therapy in a Microfluidic 3D Lung Cancer Model,” Lab on a Chip 20, no. 3 (2020): 548–557.

[183] A. Mizrak, M. F. Bolukbasi, G. B. Ozdener, et al., “Genetically Engineered Microvesicles Carrying Suicide mRNA/Protein Inhibit Schwannoma Tumor Growth,” Molecular Therapy 21, no. 1 (2013): 101–108.

[184] K. Zhang, C. Dong, M. Chen, et al., “Extracellular Vesicle-Mediated Delivery of miR-101 Inhibits Lung Metastasis in Osteosarcoma,” Theranostics 10, no. 1 (2020): 411–425.

[185] X. Shi, J. Sun, H. Li, et al., “Antitumor Efficacy of Interferon-γ-Modified Exosomal Vaccine in Prostate Cancer,” The Prostate 80, no. 11 (2020): 811–823.

[186] E. B. Ribeiro, P. G. F. de Marchi, A. C. Honorio-França, et al., “Interferon-Gamma Carrying Nanoemulsion With Immunomodulatory and Anti-Tumor Activities,” Journal of Biomedical Materials Research Part A 108, no. 2 (2020): 234–245.

[187] S. Yan, Z. Luo, Z. Li, et al., “Improving Cancer Immunotherapy Outcomes Using Biomaterials,” Angewandte Chemie International Edition 59, no. 40 (2020): 17332–17343.

[188] J. Bu, A. Nair, M. Iida, et al., “An Avidity-Based PD-L1 Antagonist Using Nanoparticle-Antibody Conjugates for Enhanced Immunotherapy,” Nano Letters 20, no. 7 (2020): 4901–4909.

[189] S. Y. Li, Y. Liu, C. F. Xu, et al., “Restoring Anti-Tumor Functions of T Cells via Nanoparticle-Mediated Immune Checkpoint Modulation,” Journal of Controlled Release 231 (2016): 17–28.

[190] L. Liu, Y. Wang, L. Miao, et al., “Combination Immunotherapy of MUC1 mRNA Nano-Vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer,” Molecular Therapy 26, no. 1 (2018): 45–55.

[191] C. Nieto, M. A. Vega, and E. M. Martín del Valle, “Trastuzumab: More Than a Guide in HER2-Positive Cancer Nanomedicine,” Nanomaterials 10, no. 9 (2020): 1674.

[192] L. A. J. O'Neill, R. J. Kishton, and J. Rathmell, “A Guide to Immunometabolism for Immunologists,” Nature Reviews Immunology 16, no. 9 (2016): 553–565..

[193] B. Kalyanaraman, “Exploiting the Tumor Immune Microenvironment and Immunometabolism Using Mitochondria-Targeted Drugs,” FASEB Journal 36, no. 4 (2022): e22226.

[194] C. H. Chang, J. D. Curtis, L. B. Maggi, et al., “Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis,” Cell 153, no. 6 (2013): 1239–1251.

[195] C. Wu, T. Xu, H. Zhang, et al., “Hypoxia and Immunometabolism in the Tumor Microenvironment: Insights Into Mechanisms and Therapeutic Potential,” Cancer Letters 631 (2025): 217913.

[196] H. Zhang, J. Fan, D. Kong, et al., “Immunometabolism: Crosstalk With Tumor Metabolism and Implications for Cancer Immunotherapy,” Molecular Cancer 24, no. 1 (2025): 249.

[197] F. Khan, Y. Lin, H. Ali, et al., “Lactate Dehydrogenase A Regulates Tumor-Macrophage Symbiosis to Promote Glioblastoma Progression,” Nature Communications 15, no. 1 (2024): 1987.

[198] G. Zheng, J. Shi, Q. Li, et al., “BAP1 Inactivation Promotes Lactate Production by Leveraging the Subcellular Localization of LDHA in Melanoma,” Cell Death Discovery 10, no. 1 (2024): 483.

[199] M. Du, T. Yu, Q. Zhan, et al., “Development of a Novel Lactate Dehydrogenase a Inhibitor With Potent Antitumor Activity and Immune Activation,” Cancer Science 113, no. 9 (2022): 2974–2985.

[200] Z. Wang, X. Li, and X. Sun, “Targeting Cholesterol Metabolism in Tumor and Its Immune Microenvironment: Opportunities and Challenges,” Biochimica et Biophysica Acta—Reviews on Cancer 1880, no. 5 (2025): 189422.

[201] H. Shen, B. Liu, J. He, et al., “Lactate Metabolic Reprogramming Mediated by circRNA–LDHA Complex Facilitates Innate Immune Evasion of Liver Cancer,” Advanced Science 12, no. 45 (2025): e09989.

[202] A. Malla, S. Gupta, and R. Sur, “Inhibition of Lactate Dehydrogenase A by Diclofenac Sodium Induces Apoptosis in HeLa Cells Through Activation of AMPK,” FEBS Journal 291, no. 16 (2024): 3628–3652.

[203] D. Nan, W. Yao, L. Huang, et al., “Glutamine and Cancer: Metabolism, Immune Microenvironment, and Therapeutic Targets,” Cell Communication and Signaling 23, no. 1 (2025): 45.

[204] G. V. Long, N. Nair, D. Marbach, et al., “Neoadjuvant PD-1 and LAG-3-Targeting Bispecific Antibody and Other Immune Checkpoint Inhibitor Combinations in Resectable Melanoma,” Nature Medicine 31, no. 11 (2025): 3700–3712.

[205] R. J. Verheijden, J. S. de Groot, B. O. Fabriek, et al., “Corticosteroids for Immune-Related Adverse Events and Checkpoint Inhibitor Efficacy,” Journal of Clinical Oncology 42, no. 31 (2024): 3713–3724.

[206] S. Dong and Z. Ma, “Combination of JAK Inhibitor and Immune Checkpoint Inhibitor in Clinical Trials: A Breakthrough,” Frontiers in Immunology 15 (2024): 1459777.

[207] M. Corrado, D. Moreira, and N. Jones, “Metabolites: Fuelling the Immune Response,” Clinical and Experimental Immunology 208, no. 2 (2022): 129–131.

[208] U. Hani, V. T. Choudhary, M. Ghazwani, et al., “Nanocarriers for Delivery of Anticancer Drugs: Current Developments, Challenges, and Perspectives,” Pharmaceutics 16, no. 12 (2024): 1527.

[209] M. Yang, M. Cui, Y. Sun, et al., “Mechanisms, Combination Therapy, and Biomarkers in Cancer Immunotherapy Resistance,” Cell Communication and Signaling 22, no. 1 (2024): 338.

[210] J. Deng, A. L. Tian, H. Pan, et al., “Everolimus and Plicamycin Specifically Target Chemoresistant Colorectal Cancer Cells of the CMS4 Subtype,” Cell Death & Disease 12, no. 11 (2021): 978.

[211] M. W. Khan, D. Biswas, M. Ghosh, et al., “mTORC2 Controls Cancer Cell Survival by Modulating Gluconeogenesis,” Cell Death Discovery 1 (2015): 15016.

[212] Q. Song, J. Sui, Y. Yang, et al., “Fructose-1,6-Bisphosphatase 1 in Cancer: Dual Roles, Mechanistic Insights, and Therapeutic Potential—A Comprehensive Review,” International Journal of Biological Macromolecules 293 (2025): 139273.

[213] R. Su, C. Li, X. Wang, et al., “PPFIA1-Targeting miR-181a Mimic and saRNA Overcome Imatinib Resistance in Chronic Myeloid Leukemia,” Molecular Therapy—Nucleic Acids 32 (2023): 729–742.

[214] D. Sarker, R. Plummer, T. Meyer, et al., “MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients With Advanced Liver Cancer,” Clinical Cancer Research 26, no. 15 (2020): 3936–3946.

[215] S. Yoon, K. W. Huang, P. Andrikakou, et al., “Targeted Delivery of C/EBPα-saRNA by RNA Aptamers Shows Anti-Tumor Effects in a Mouse Model of Advanced PDAC,” Molecular Therapy—Nucleic Acids 18 (2019): 142–154.

[216] A. Hashimoto, D. Sarker, V. Reebye, et al., “Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients With Cancer,” Clinical Cancer Research 27, no. 21 (2021): 5961–5978.

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