Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment

Abstract

Highlight:

Keywords

glucose metabolic reprogramming / immunometabolism / immunosuppression / immunotherapy / tumour microenvironment / Warburg effect

References

[1] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168(4): 707-723.

[2] Arneth B. Tumor microenvironment. Medicina. 2020; 56(1): 15.

[3] Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020; 30(16): R921-R925.

[4] Wang M, Zhao J, Zhang L, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017; 8(5): 761-773.

[5] Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023; 41(3): 421-433.

[6] Zhang H, Li S, Wang D, et al. Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment. Biomark Res. 2024; 12(1): 96.

[7] Sreedhar A, Zhao Y. Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells. Biomed Rep. 2018; 8(1): 3-10.

[8] Nong S, Han X, Xiang Y, et al. Metabolic reprogramming in cancer: mechanisms and therapeutics. MedComm. 2023; 4(2):e218.

[9] Huang M, Yang L, Peng X, et al. Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy. J Exp Clin Cancer Res. 2020; 39(1): 185.

[10] DeWaal D, Nogueira V, Terry AR, et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018; 9(1): 446.

[11] Li Y, Sun XX, Qian DZ, Dai MS. Molecular Crosstalk Between MYC and HIF in Cancer. Front Cell Dev Biol. 2020; 8:590576.

[12] Zhou CH, Zhang XP, Liu F, Wang W. Modeling the interplay between the HIF-1 and p53 pathways in hypoxia. Sci Rep. 2015; 5(1):13834.

[13] Xia X, Wang S, Ni B, et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene. 2020; 39(39): 6231-6244.

[14] Chen J, Huang Z, Chen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther. 2025; 10(1): 1-26.

[15] Estrella V, Chen T, Lloyd M, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013; 73(5): 1524-1535.

[16] Demicco M, Liu XZ, Leithner K, Fendt SM. Metabolic heterogeneity in cancer. Nat Metab. 2024; 6(1): 18-38.

[17] Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics. 2021; 11(17): 8322-8336.

[18] Chai X, Tao Q, Li L. Spatiotemporal heterogeneity of tumor glucose metabolism reprogramming: from single-cell mechanisms to precision interventions. Int J Mol Sci. 2025; 26(14): 6901.

[19] Oliveira G, Wu CJ. Dynamics and specificities of T cells in cancer immunotherapy. Nat Rev Cancer. 2023; 23(5): 295-316.

[20] Herbel C, Patsoukis N, Bardhan K, Seth P, Weaver JD, Boussiotis VA. Clinical significance of T cell metabolic reprogramming in cancer. Clin Transl Med. 2016; 5(1): 29.

[21] Yin Z, Bai L, Li W, Zeng T, Tian H, Cui J. Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy. J Exp Clin Cancer Res. 2019; 38(1): 403.

[22] Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35(6): 871-882.

[23] Zhou X, Fang D, Liu H, et al. PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer. Cancer Lett. 2022; 532:215598.

[24] Prasad M, Brzostek J, Gautam N, Balyan R, Rybakin V, Gascoigne NRJ. Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation. Cell Mol Immunol. 2021; 18(9): 2249-2261.

[25] Qin J, Liu Q, Liu A, et al. Empagliflozin modulates CD4+ T-cell differentiation via metabolic reprogramming in immune thrombocytopenia. Br J Haematol. 2022; 198(4): 765-775.

[26] Blanco R, Gómez de Cedrón M, Gámez-Reche L, et al. The chemokine receptor CCR5 links memory CD4+ T cell metabolism to T cell antigen receptor nanoclustering. Front Immunol. 2021; 12:722320.

[27] Liu S, Liao S, Liang L, Deng J, Zhou Y. The relationship between CD4+ T cell glycolysis and their functions. Trends Endocrinol Metab. 2023; 34(6): 345-360.

[28] Zhang T, Zhang Z, Li F, et al. miR-143 regulates memory T cell differentiation by reprogramming T cell metabolism. J Immunol. 2018; 201(7): 2165-2175.

[29] Shen H, Ojo OA, Ding H, et al. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nat Commun. 2024; 15(1): 9394.

[30] Lv Q, Su T, Liu W, et al. Low serum apolipoprotein A1 levels impair antitumor immunity of CD8+ T cells via the HIF-1α–glycolysis pathway. Cancer Immunol Res. 2024; 12(8): 1058-1073.

[31] Li Q, Yan Y, Liu J, et al. Toll-like receptor 7 activation enhances CD8+ T cell effector functions by promoting cellular glycolysis. Front Immunol. 2019; 10: 2191.

[32] Xu K, Yin N, Peng M, et al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science. 2021; 371(6527): 405-410.

[33] Renner K, Geiselhöringer AL, Fante M, et al. Metabolic plasticity of human T cells: preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions. Eur J Immunol. 2015; 45(9): 2504-2516.

[34] Amitrano AM, Berry BJ, Lim K, et al. Optical control of CD8+ T cell metabolism and effector functions. Front Immunol. 2021; 12:666231.

[35] Slack M, Wang T, Wang R. T cell metabolic reprogramming and plasticity. Mol Immunol. 2015; 68(2): 507-512.

[36] Vardhana SA, Hwee MA, Berisa M, et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat Immunol. 2020; 21(9): 1022-1033.

[37] Chang CH, Curtis JD, Maggi LB, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013; 153(6): 1239-1251.

[38] Bengsch B, Johnson AL, Kurachi M, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by PD-1 are an early driver of CD8+ T cell exhaustion. Immunity. 2016; 45(2): 358-373.

[39] Scharping NE, Rivadeneira DB, Menk AV, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021; 22(2): 205-215.

[40] Murphy TL, Murphy KM. Dendritic cells in cancer immunology. Cell Mol Immunol. 2022; 19(1): 3-13.

[41] Everts B, Amiel E, Huang SCC, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014; 15(4): 323-332.

[42] Thwe PM, Pelgrom LR, Cooper R, et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses. Cell Metab. 2017; 26(3): 558-567.e5.

[43] Guak H, Al Habyan S, Ma EH, et al. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat Commun. 2018; 9(1): 2463.

[44] Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cell Mol Immunol. 2021; 18(11): 2461-2471.

[45] Maio M, Barros J, Joly M, et al. Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis. eLife. 2024; 12:RP89319.

[46] Liu J, Zhang X, Chen K, et al. CCR7 chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis. Immunity. 2019; 50(3): 600-615.e15.

[47] de Lima Thomaz L, Peron G, Oliveira J, daRosa LC, Thomé R, Verinaud L. The impact of metabolic reprogramming on dendritic cell function. Int Immunopharmacol. 2018; 63: 84-93.

[48] Ryans K, Omosun Y, McKeithen DN, et al. The immunoregulatory role of alpha enolase in dendritic cell function during Chlamydia infection. BMC Immunol. 2017; 18(1): 27.

[49] Inamdar S, Suresh AP, Mangal JL, et al. Rescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice. Nat Commun. 2023; 14(1): 5333.

[50] Hu Z, Yu X, Ding R, et al. Glycolysis drives STING signaling to facilitate dendritic cell antitumor function. J Clin Invest. 2023; 133(7):e166031.

[51] Everts B, Amiel E, van der Windt GJW, et al. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood. 2012; 120(7): 1422-1431.

[52] Lawless SJ, Kedia-Mehta N, Walls JF, et al. Glucose represses dendritic cell-induced T cell responses. Nat Commun. 2017; 8(1):15620.

[53] Giovanelli P, Sandoval TA, Cubillos-Ruiz JR. Dendritic cell metabolism and function in tumors. Trends Immunol. 2019; 40(8): 699-718.

[54] Zhao Y, Gao C, Liu L, Wang L, Song Z. The development and function of human monocyte-derived dendritic cells regulated by metabolic reprogramming. J Leukoc Biol. 2023; 114(3): 212-222.

[55] Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLOS Biol. 2014; 12(1):e1001759.

[56] Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021; 18(2): 85-100.

[57] Terrén I, Orrantia A, Mosteiro A, Vitallé J, Zenarruzabeitia O, Borrego F. Metabolic changes of interleukin-12/15/18-stimulated human NK cells. Sci Rep. 2021; 11(1): 6472.

[58] O'Brien KL, Finlay DK. Immunometabolism and natural killer cell responses. Nat Rev Immunol. 2019; 19(5): 282-290.

[59] Assmann N, O'Brien KL, Donnelly RP, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol. 2017; 18(11): 1197-1206.

[60] Loftus RM, Assmann N, Kedia-Mehta N, et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat Commun. 2018; 9(1): 2341.

[61] He H, Song Z, Lin S, Wang Y, Wang G. Exploring the effect of polyamines on NK cell function in colorectal cancer process based on glycolysis. Int Immunopharmacol. 2023; 117:109944.

[62] Mah AY, Rashidi A, Keppel MP, et al. Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control. JCI Insight. 2017; 2(23):e95128.

[63] Donnelly RP, Loftus RM, Keating SE, et al. mTORC1-dependent metabolic reprogramming is a prerequisite for natural killer cell effector function. J Immunol. 2014; 193(9): 4477-4484.

[64] Marçais A, Cherfils-Vicini J, Viant C, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014; 15(8): 749-757.

[65] Keating SE, Zaiatz-Bittencourt V, Loftus RM, et al. Metabolic reprogramming supports IFN-γ production by CD56bright NK cells. J Immunol. 2016; 196(6): 2552-2560.

[66] Wang Z, Guan D, Wang S, Chai LYA, Xu S, Lam KP. Glycolysis and oxidative phosphorylation play critical roles in natural killer cell receptor-mediated natural killer cell functions. Front Immunol. 2020; 11: 202.

[67] Shan F, Somasundaram A, Bruno TC, Workman CJ, Vignali DAA. Therapeutic targeting of regulatory T cells in cancer. Trends Cancer. 2022; 8(11): 944-961.

[68] Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol. 2015; 16(2): 178-187.

[69] Patterson SJ, Han JM, Garcia R, et al. Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol. 2011; 186(10): 5533-5537.

[70] Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A. Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. Int Immunol. 2018; 30(8): 357-373.

[71] Angelin A, Gil-de-Gómez L, Dahiya S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017; 25(6): 1282-1293.e7.

[72] Gerriets VA, Kishton RJ, Johnson MO, et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol. 2016; 17(12): 1459-1466.

[73] Kishore M, Cheung KCP, Fu H, et al. Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity. 2017; 47(5): 875-889.e10.

[74] Miska J, Lee-Chang C, Rashidi A, et al. HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of Tregs in glioblastoma. Cell Rep. 2019; 27(1): 226-237.e4.

[75] Pacella I, Procaccini C, Focaccetti C, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci. 2018; 115(28): E6546-E6555.

[76] Bai J, Yan M, Xu Y, et al. YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix. J Immunother Cancer. 2024; 12(11):e010463.

[77] Lowe MM, Boothby I, Clancy S, et al. Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. 2019; 4(24):e129756.

[78] Field CS, Baixauli F, Kyle RL, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab. 2020; 31(2): 422-437.e5.

[79] Li L, Liu X, Sanders KL, et al. TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy. Cell Metab. 2019; 29(1): 103-123.e5.

[80] Sun IH, Oh MH, Zhao L, et al. mTOR complex 1 signaling regulates the generation and function of central and effector Foxp3+ regulatory T cells. J Immunol. 2018; 201(2): 481-492.

[81] Kumari N, Choi SH. Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies. J Exp Clin Cancer Res. 2022; 41(1): 68.

[82] Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol. 2015; 34(1): 82-100.

[83] Andrejeva G, Rathmell JC. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 2017; 26(1): 49-70.

[84] M de-Brito N, Duncan-Moretti J, C da-Costa H, et al. Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages. Biochim Biophys Acta Mol Cell Res. 2020; 1867(2):118604.

[85] Jiang Y, Han Q, Zhao H, Zhang J. Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis. J Exp Clin Cancer Res. 2021; 40(1): 13.

[86] Ning WR, Jiang D, Liu XC, et al. Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma. J Clin Invest. 2022; 132(7):e153110.

[87] Cai Z, Li W, Hager S, et al. Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling. Cell Mol Immunol. 2024; 21(5): 448-465.

[88] Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019; 30(1): 36-50.

[89] Liu Y, Liu D, Liu Y, et al. Comprehensive proteomics analysis reveals dynamic phenotypes of tumor-associated macrophages and their precursor cells in tumor progression. J Proteome Res. 2024; 23(2): 822-833.

[90] Penny HL, Sieow JL, Adriani G, et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. OncoImmunology. 2016; 5(8):e1191731.

[91] Arts RJW, Plantinga TS, Tuit S, et al. Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages. OncoImmunology. 2016; 5(12):e1229725.

[92] Wenes M, Shang M, Di Matteo M, et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 2016; 24(5): 701-715.

[93] Wang Y, Wang D, Yang L, Zhang Y. Metabolic reprogramming in the immunosuppression of tumor-associated macrophages. Chin Med J. 2022; 135(20): 2405.

[94] Miller A, Nagy C, Knapp B, et al. Exploring metabolic configurations of single cells within complex tissue microenvironments. Cell Metab. 2017; 26(5): 788-800.e6.

[95] Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol. 2024; 21(2): 147-164.

[96] Hu C, Pang B, Lin G, Zhen Y, Yi H. Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells. Br J Cancer. 2020; 122(1): 23-29.

[97] Li X, Li Y, Yu Q, Qian P, Huang H, Lin Y. Metabolic reprogramming of myeloid-derived suppressor cells: an innovative approach confronting challenges. J Leukoc Biol. 2021; 110(2): 257-270.

[98] Jian SL, Chen WW, Su YC, et al. Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis. 2017; 8(5): e2779-e2779.

[99] Fu C, Fu Z, Jiang C, et al. CD205+ polymorphonuclear myeloid-derived suppressor cells suppress antitumor immunity by overexpressing GLUT3. Cancer Sci. 2021; 112(3): 1011-1025.

[100] Wang H, Zhou F, Qin W, Yang Y, Li X, Liu R. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies. Theranostics. 2025; 15(6): 2159-2184.

[101] Patel S, Fu S, Mastio J, et al. Unique pattern of neutrophil migration and function during tumor progression. Nat Immunol. 2018; 19(11): 1236-1247.

[102] Sica A, Strauss L. Energy metabolism drives myeloid-derived suppressor cell differentiation and functions in pathology. J Leukoc Biol. 2017; 102(2): 325-334.

[103] Porta C, Marino A, Consonni FM, et al. Metabolic influence on the differentiation of suppressive myeloid cells in cancer. Carcinogenesis. 2018; 39(9): 1095-1104.

[104] Wu T, Zhao Y, Wang H, et al. mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors. Sci Rep. 2016; 6(1):20250.

[105] Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010; 207(11): 2439-2453.

[106] Mohammadpour H, MacDonald CR, McCarthy PL, Abrams SI, Repasky EA. β2-adrenergic receptor signaling regulates metabolic pathways critical to myeloid-derived suppressor cell function within the TME. Cell Rep. 2021; 37(4):109883.

[107] Niu Y, Mayr T, Muders MH. Competition for nutrients or cell intrinsic programming?—Metabolic mechanisms behind the tumor promoting immune microenvironment in cancer. Signal Transduct Target Ther. 2021; 6(1): 279.

[108] Chang CH, Qiu J, O'Sullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015; 162(6): 1229-1241.

[109] Wu L, Jin Y, Zhao X, et al. Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α. Cell Metab. 2023; 35(9): 1580-1596.e9.

[110] Guerrero JA, Klysz DD, Chen Y, et al. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nat Commun. 2024; 15(1): 8658.

[111] Shi Y, Kotchetkov IS, Dobrin A, et al. GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy. Mol Ther. 2024; 32(7): 2393-2405.

[112] Schild T, Wallisch P, Zhao Y, et al. Metabolic engineering to facilitate anti-tumor immunity. Cancer Cell. 2025; 43(3): 552-562.e9.

[113] Zhu J, Yang W, Zhou X, et al. High glucose enhances cytotoxic T lymphocyte-mediated cytotoxicity. Front Immunol. 2021; 12:689337.

[114] Kim J, Kim Y, La J, et al. Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation. Cell Rep. 2023; 42(10):113220.

[115] Zhang D, Jin W, Wu R, et al. High glucose intake exacerbates autoimmunity through reactive-oxygen-species-mediated TGF-β cytokine activation. Immunity. 2019; 51(4): 671-681.e5.

[116] Zhang B, Ohuchida K, Tsutsumi C, et al. Dynamic glycolytic reprogramming effects on dendritic cells in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res. 2024; 43(1): 271.

[117] Sun H, Zhang H, Jing L, Zhao H, Chen B, Song W. FBP1 is a potential prognostic biomarker and correlated with tumor immunosuppressive microenvironment in glioblastoma. Neurosurg Rev. 2023; 46(1): 187.

[118] Leprivier G, Rotblat B. How does mTOR sense glucose starvation? AMPK is the usual suspect. Cell Death Discov. 2020; 6(1): 1-5.

[119] Thomas AM, Dong Y, Beskid NM, García AJ, Adams AB, Babensee JE. Brief exposure to hyperglycemia activates dendritic cells in vitro and in vivo. J Cell Physiol. 2020; 235(6): 5120-5129.

[120] Lu H, Yao K, Huang D, et al. High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells. Cardiovasc Diabetol. 2013; 12(1): 80.

[121] Cong J, Wang X, Zheng X, et al. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab. 2018; 28(2): 243-255.e5.

[122] Han F, Guo S, Huang C, et al. Gastric cancer mesenchymal stem cells inhibit natural killer cell function by up-regulating FBP1. Cent Eur J Immunol. 2021; 46(4): 427-437.

[123] Kobayashi T, Mattarollo SR. Natural killer cell metabolism. Mol Immunol. 2019; 115: 3-11.

[124] Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018; 27(2): 299-313.

[125] Picard LK, Littwitz-Salomon E, Waldmann H, Watzl C. Inhibition of glucose uptake blocks proliferation but not cytotoxic activity of NK cells. Cells. 2022; 11(21): 21.

[126] Ehlers FAI, Mahaweni NM, Olieslagers TI, Bos GMJ, Wieten L. Activated natural killer cells withstand the relatively low glucose concentrations found in the bone marrow of multiple myeloma patients. Front Oncol. 2021; 11:622896.

[127] Pan X, Wang J, Zhang L, Li G, Huang B. Metabolic plasticity of T cell fate decision. Chin Med J. 2024; 137(07): 762-775.

[128] Howie D, Cobbold SP, Adams E, et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight. 2017; 2(3):e89160.

[129] Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature. 2013; 499(7459): 485-490.

[130] Clambey ET, McNamee EN, Westrich JA, et al. Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci. 2012; 109(41): E2784-E2793.

[131] Reinfeld BI, Madden MZ, Wolf MM, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021; 593(7858): 282-288.

[132] Blatt S, Voelxen N, Sagheb K, et al. Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: a prospective study over 15 years. Clin Oral Investig. 2016; 20(8): 2097-2104.

[133] Cheung SM, Husain E, Masannat Y, et al. Lactate concentration in breast cancer using advanced magnetic resonance spectroscopy. Br J Cancer. 2020; 123(2): 261-267.

[134] Quinn WJ, Jiao J, TeSlaa T, et al. Lactate limits T cell proliferation via the NAD(H) redox state. Cell Rep. 2020; 33(11):108500.

[135] Liu Y, Wang F, Peng D, et al. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid. Sci Transl Med. 2024; 16(762):eadk7399.

[136] Chen Y, Feng Z, Kuang X, et al. Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8+ cytolytic T cells. Am J Cancer Res. 2021; 11(11): 5726-5742.

[137] Khan O, Giles JR, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature. 2019; 571(7764): 211-218.

[138] Peralta RM, Xie B, Lontos K, et al. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat Immunol. 2024; 25(12): 2297-2307.

[139] Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017; 551(7678): 115-118.

[140] Ma J, Tang L, Tan Y, et al. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria. Nat Immunol. 2024; 25(3): 552-561.

[141] Caronni N, Simoncello F, Stafetta F, et al. Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer. Cancer Res. 2018; 78(7): 1685-1699.

[142] Wang ZH, Peng WB, Zhang P, Yang XP, Zhou Q. Lactate in the tumour microenvironment: from immune modulation to therapy. eBioMedicine. 2021; 73:103627.

[143] Kanemaru H, Mizukami Y, Kaneko A, et al. A mechanism of cooling hot tumors: lactate attenuates inflammation in dendritic cells. iScience. 2021; 24(9):103067.

[144] Sangsuwan R, Thuamsang B, Pacifici N, et al. Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells. Heliyon. 2025; 11(3):e42098.

[145] Plebanek MP, Xue Y, Nguyen YV, et al. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 2024; 9(95):eadi4191. Published online May 10, 2024.

[146] Brand A, Singer K, Koehl GE, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016; 24(5): 657-671.

[147] Gu XY, Yang JL, Lai R, et al. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol. 2025; 16:1563303.

[148] Jin J, Yan P, Wang D, et al. Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment. Nat Immunol. 2025; 26(7): 1099-1112.

[149] Claps G, Faouzi S, Quidville V, et al. The multiple roles of LDH in cancer. Nat Rev Clin Oncol. 2022; 19(12): 749-762.

[150] Harmon C, Robinson MW, Hand F, et al. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis. Cancer Immunol Res. 2019; 7(2): 335-346.

[151] Kondo M, Kumagai S, Nishikawa H. Metabolic advantages of regulatory T cells dictated by cancer cells. Int Immunol. 2024; 36(2): 75-86.

[152] Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851): 645-651.

[153] Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022; 40(2): 201-218.e9.

[154] Gu J, Zhou J, Chen Q, et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep. 2022; 39(12):110986.

[155] Xue Q, Peng W, Zhang S, et al. Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion. J Immunother Cancer. 2024; 12(12):e010040.

[156] Rao D, Stunnenberg JA, Lacroix R, et al. Acidity-mediated induction of FoxP3+ regulatory T cells. Eur J Immunol. 2023; 53(6):e2250258.

[157] Kes MMG, Van den Bossche J, Griffioen AW, Huijbers EJM. Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors. Biochim Biophys Acta Rev Cancer. 2020; 1874(2):188427.

[158] Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513(7519): 559-563.

[159] Mu X, Shi W, Xu Y, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018; 17(4): 428-438.

[160] Liu N, Luo J, Kuang D, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J Clin Invest. 2019; 129(2): 631-646.

[161] Chen P, Zuo H, Xiong H, et al. Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci. 2017; 114(3): 580-585.

[162] Cheng WY, Huynh H, Chen P, Peña-Llopis S, Wan Y. Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone. eLife. 2016; 5:e18501.

[163] Vadevoo SMP, Gunassekaran GR, Lee C, et al. The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci. 2021; 118(37):e2102434118.

[164] Gao X, Zhou S, Qin Z, Li D, Zhu Y, Ma D. Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression. J Transl Med. 2023; 21(1): 53.

[165] Zhao JL, Ye YC, Gao CC, et al. Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell Rep. 2022; 38(10):110451.

[166] Yang X, Lu Y, Hang J, et al. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res. 2020; 8(11): 1440-1451.

[167] Vander Ark A, Cao J, Li X. TGF-β receptors: in and beyond TGF-β signaling. Cell Signal. 2018; 52: 112-120.

[168] Shi X, Yang J, Deng S, et al. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol. 2022; 15(1): 135.

[169] Huang Y, Chen Z, Lu T, et al. HIF-1α switches the functionality of TGF-β signaling via changing the partners of Smads to drive glucose metabolic reprogramming in non-small cell lung cancer. J Exp Clin Cancer Res. 2021; 40: 398.

[170] Hope HC, Pickersgill G, Ginefra P, Vannini N, Cook GP, Salmond RJ. TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells. Front Immunol. 2022; 13:913184.

[171] Gabriel SS, Tsui C, Chisanga D, et al. Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity. 2021; 54(8): 1698-1714.e5.

[172] Gunderson AJ, Yamazaki T, McCarty K, et al. TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking. Nat Commun. 2020; 11(1): 1749.

[173] Sim WJ, Ahl PJ, Connolly JE. Metabolism is central to tolerogenic dendritic cell function. Mediators Inflamm. 2016; 2016:2636701.

[174] Imai K, Minamiya Y, Koyota S, et al. Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis. J Exp Clin Cancer Res. 2012; 31(1): 3.

[175] Slattery K, Woods E, Zaiatz-Bittencourt V, et al. TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer. J Immunother Cancer. 2021; 9(2):e002044.

[176] Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type I and type III interferons. Immunity. 2019; 50(4): 907-923.

[177] Cham CM, Gajewski TF. Glucose availability regulates IFN-γ production and p70S6 kinase activation in CD8+ effector T cells. J Immunol. 2005; 174(8): 4670-4677.

[178] Keppel MP, Saucier N, Mah AY, Vogel TP, Cooper MA. Activation-specific metabolic requirements for NK cell IFN-γ production. J Immunol. 2015; 194(4): 1954-1962.

[179] Zeng Z, Veitch M, Kelly GA, et al. IFN-γ critically enables the intratumoural infiltration of CXCR3+ CD8+ T cells to drive squamous cell carcinoma regression. Cancers. 2021; 13(9): 2131.

[180] Yan Y, Zheng L, Du Q, et al. Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC). Cancer Lett. 2021; 506: 95-106.

[181] Chattopadhyay A, Jagdish S, Karhale AK, Ramteke NS, Zaib A, Nandi D. IFN-γ lowers tumor growth by increasing glycolysis and lactate production in a nitric oxide-dependent manner: implications for cancer immunotherapy. Front Immunol. 2023; 14:1282653.

[182] Numata Y, Akutsu N, Ishigami K, et al. Synergistic effect of IFN-γ and IL-1β on PD-L1 expression in hepatocellular carcinoma. Biochem Biophys Rep. 2022; 30:101270.

[183] Wu M, Huang Q, Xie Y, et al. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J Hematol Oncol. 2022; 15(1): 24.

[184] Hubert M, Gobbini E, Couillault C, et al. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer. Sci Immunol. 2020; 5(46):eaav3942.

[185] He QQ, Huang Y, Nie L, et al. MAVS integrates glucose metabolism and RIG-I-like receptor signaling. Nat Commun. 2023; 14(1): 5343.

[186] Larsen TV, Daugaard TF, Gad HH, Hartmann R, Nielsen AL. PD-L1 and PD-L2 immune checkpoint protein induction by type III interferon in non-small cell lung cancer cells. Immunobiology. 2023; 228(3):152389.

[187] Jones CV, Ricardo SD. Macrophages and CSF-1. Organogenesis. 2013; 9(4): 249-260.

[188] Chaturvedi P, Gilkes DM, Takano N, Semenza GL. Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci. 2014; 111(20): E2120-E2129.

[189] Franklin DA, Sharick JT, Ericsson-Gonzalez PI, et al. MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC. JCI Insight. 2020; 5(15):e134290.

[190] Li M, Wang M, Wen Y, Zhang H, Zhao G, Gao Q. Signaling pathways in macrophages: molecular mechanisms and therapeutic targets. MedComm. 2023; 4(5):e349.

[191] Huang SCC, Smith AM, Everts B, et al. mTORC2-IRF4 mediated metabolic reprograming is essential for macrophage alternative activation. Immunity. 2016; 45(4): 817-830.

[192] Na YR, Hong JH, Lee MY, et al. Proteomic analysis reveals distinct metabolic differences between granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF) grown macrophages derived from murine bone marrow cells. Mol Cell Proteomics. 2015; 14(10): 2722-2732.

[193] Gharzeddine K, Gonzalez Prieto C, Malier M, et al. Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers. J Immunother Cancer. 2024; 12(9):e009602.

[194] Huang Z, Guo Y, Li B, et al. Siglec-15 on macrophages suppress the immune microenvironment in patients with PD-L1 negative non-metastasis lung adenocarcinoma. Cancer Gene Ther. 2024; 31(3): 427-438.

[195] Kaneda MM, Messer KS, Ralainirina N, et al. PI3Kγ is a molecular switch that controls immune suppression. Nature. 2016; 539(7629): 437-442.

[196] Phan VT, Wu X, Cheng JH, et al. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF–induced neutrophil recruitment. Proc Natl Acad Sci. 2013; 110(15): 6079-6084.

[197] Li W, Tanikawa T, Kryczek I, et al. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab. 2018; 28(1): 87-103.e6.

[198] Thorn M, Guha P, Cunetta M, et al. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther. 2016; 23(6): 188-198.

[199] Na YR, Gu GJ, Jung D, et al. GM-CSF induces inflammatory macrophages by regulating glycolysis and lipid metabolism. J Immunol. 2016; 197(10): 4101-4109.

[200] Bhattacharya P, Budnick I, Singh M, et al. Dual role of GM-CSF as a pro-inflammatory and a regulatory cytokine: implications for immune therapy. J Interferon Cytokine Res. 2015; 35(8): 585-599.

[201] Qian BZ, Li J, Zhang H, et al. CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis. Nature. 2011; 475(7355): 222-225.

[202] Sun K, Zhang X, Shi J, et al. Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma. J Clin Invest. 2025; 135(7):e187024.

[203] Fei L, Ren X, Yu H, Zhan Y. Targeting the CCL2/CCR2 axis in cancer immunotherapy: one stone, three birds? Front Immunol. 2021; 12:771210.

[204] Yang H, Zhang Q, Xu M, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020; 19(1): 41.

[205] Chun E, Lavoie S, Michaud M, et al. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep. 2015; 12(2): 244-257.

[206] Molon B, Ugel S, Del Pozzo F, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med. 2011; 208(10): 1949-1962.

[207] Yang K, Xu J, Fan M, et al. Lactate suppresses macrophage pro-inflammatory response to LPS stimulation by inhibition of YAP and NF-κB activation via GPR81-mediated signaling. Front Immunol. 2020; 11:587913.

[208] Tan Q, Duan L, Huang Q, et al. Interleukin -1β promotes lung adenocarcinoma growth and invasion through promoting glycolysis via p38 pathway. J Inflamm Res. 2021; 14: 6491-6509.

[209] Vaughan RA, Garcia-Smith R, Trujillo KA, Bisoffi M. Tumor necrosis factor alpha increases aerobic glycolysis and reduces oxidative metabolism in prostate epithelial cells. The Prostate. 2013; 73(14): 1538-1546.

[210] Han J, Meng Q, Xi Q, et al. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer. Int J Oncol. 2016; 48(1): 215-224.

[211] Laha D, Grant R, Mishra P, Nilubol N. The role of tumor necrosis factor in manipulating the immunological response of tumor microenvironment. Front Immunol. 2021; 12:656908.

[212] Li XN, Peng YH, Yue W, Tao L, Zhang WJ. A cohort study using IL-6/Stat3 activity and PD-1/PD-L1 expression to predict five-year survival for patients after gastric cancer resection. PLOS ONE. 2022; 17(12):e0277908.

[213] Nawas AF, Solmonson A, Gao B, et al. IL-1β mediates the induction of immune checkpoint regulators IDO1 and PD-L1 in lung adenocarcinoma cells. Cell Commun Signal. 2023; 21(1): 331.

[214] Meraviglia-Crivelli D, Villanueva H, Zheleva A, et al. IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction. Mol Cancer. 2022; 21(1): 211.

[215] Hayden MS, Ghosh S. Regulation of NF-κB by TNF Family Cytokines. Semin Immunol. 2014; 26(3): 253-266.

[216] Xu B, Liu Y, Li N, Geng Q. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol. 2024; 15:1395786.

[217] Du F, Qi X, Zhang A, et al. MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β. Exp Mol Med. 2021; 53(9): 1366-1378.

[218] Hazini A, Fisher K, Seymour L. Deregulation of HLA-I in cancer and its central importance for immunotherapy. J Immunother Cancer. 2021; 9(8):e002899.

[219] Jeong H, Koh J, Kim S, et al. Epithelial−mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer. Br J Cancer. 2024; 131(1): 23-36.

[220] Wang F, Zhang S, Jeon R, et al. Interferon gamma induces reversible metabolic reprogramming of M1 macrophages to sustain cell viability and pro-inflammatory activity. EBioMedicine. 2018; 30: 303-316.

[221] Mantel I, Sadiq BA, Blander JM. Spotlight on TAP and its vital role in antigen presentation and cross-presentation. Mol Immunol. 2022; 142: 105-119.

[222] Hawley KL, Cruz AR, Benjamin SJ, et al. IFNγ enhances CD64-potentiated phagocytosis of Treponema pallidum opsonized with human syphilitic serum by human macrophages. Front Immunol. 2017; 8: 1227.

[223] Zhang X, Zeng Y, Qu Q, 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. Int J Clin Oncol. 2017; 22(6): 1026-1033.

[224] Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res. 2011; 51(2): 170-182.

[225] Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumor-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851): 645-651.

[226] Sawant DV, Yano H, Chikina M, et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol. 2019; 20(6): 724-735.

[227] Sun Z, Fourcade J, Pagliano O, et al. IL-10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T cells. Cancer Res. 2015; 75(8): 1635-1644.

[228] Krawczyk CM, Holowka T, Sun J, et al. Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010; 115(23): 4742-4749.

[229] Clark SE, Burrack KS, Jameson SC, Hamilton SE, Lenz LL. NK cell IL-10 production requires IL-15 and IL-10 driven STAT3 activation. Front Immunol. 2019; 10: 2087.

[230] Guo Y, Xie YQ, Gao M, et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat Immunol. 2021; 22(6): 746-756.

[231] Qiu Z, Chu TH, Sheridan BS. TGF-β: many paths to CD103+ CD8 T cell residency. Cells. 2021; 10(5): 989.

[232] Liu B, Wu Y, Xiang A, et al. The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level. Cell Rep. 2025; 44(9):116249.

[233] Kaufman B, Abu-Ahmad M, Radinsky O, et al. N-glycosylation of PD-L1 modulates the efficacy of immune checkpoint blockades targeting PD-L1 and PD-1. Mol Cancer. 2025; 24: 140.

[234] Guo X, Cui T, Sun L, et al. A STT3A-dependent PD-L1 glycosylation modification mediated by GMPS drives tumor immune evasion in hepatocellular carcinoma. Cell Death Differ. 2025; 32(5): 944-958.

[235] Duan Z, Shi R, Gao B, Cai J. N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment. J Transl Med. 2024; 22(1): 705.

[236] Chi JJ, Xie P, Cheng MH, et al. MGAT1-Guided complex N-Glycans on CD73 regulate immune evasion in triple-negative breast cancer. Nat Commun. 2025; 16(1): 3552.

[237] Egan H, Treacy O, Lynch K, et al. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. Cell Rep. 2023; 42(5):112475.

[238] Garnham R, Geh D, Nelson R, et al. ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer. Commun Biol. 2024; 7(1): 276.

[239] Krishnamoorthy V, Daly J, Kim J, et al. The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9. Leukemia. 2025; 39(2): 346-359.

[240] Boelaars K, Rodriguez E, Huinen ZR, et al. Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions. Commun Biol. 2024; 7(1): 430.

[241] Saini P, Mirji G, Islam SMS, et al. Targeting interactions between Siglec-10 and α3β1 integrin enhances macrophage-mediated phagocytosis of pancreatic cancer. Cancer Res. 2026; 86(1): 99-115.

[242] Ma Z, Hao X, Qu S, et al. Siglec-15 antibody–GM-CSF chimera suppresses tumor progression via reprogramming tumor-associated macrophages. J Immunother Cancer. 2025; 13(4):e010580.

[243] Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells. Cell Res. 2020; 30(8): 649-659.

[244] Zheng L, Yang Q, Li F, et al. The glycosylation of immune checkpoints and their applications in oncology. Pharmaceuticals. 2022; 15(12): 1451.

[245] Sun L, Li CW, Chung EM, et al. Targeting glycosylated PD-1 induces potent anti-tumor immunity. Cancer Res. 2020; 80(11): 2298-2310.

[246] Chu CW, Čaval T, Alisson-Silva F, et al. Variable PD-1 glycosylation modulates the activity of immune checkpoint inhibitors. Life Sci Alliance. 2024; 7(3):e202302368.

[247] Pan B, Chen S, Wu H, et al. Short-term starvation inhibits CD36 N-glycosylation and downregulates USP7 UFMylation to alleviate RBPJ-maintained T cell exhaustion in liver cancer. Theranostics. 2025; 15(12): 5931-5952.

[248] Smith LK, Boukhaled GM, Condotta SA, et al. Interleukin-10 directly inhibits CD8+ T cell function by enhancing N-glycan branching to decrease antigen sensitivity. Immunity. 2018; 48(2): 299-312.e5.

[249] Zhou J, Gu J, Qian Q, et al. Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria. J Clin Invest. 2024; 134(20):e175897.

[250] Shi Q, Shen Q, Liu Y, et al. Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance. Cancer Cell. 2022; 40(10): 1207-1222.e10.

[251] Lin J, Fang W, Xiang Z, et al. Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion. Front Immunol. 2023; 14:1189953.

[252] Guo D, Tong Y, Jiang X, et al. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell Metab. 2022; 34(9): 1312-1324.e6.

[253] Xia Q, Jia J, Hu C, et al. Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma. Oncogene. 2022; 41(6): 865-877.

[254] Chen M, Liu H, Li Z, Ming AL, Chen H. Mechanism of PKM2 affecting cancer immunity and metabolism in tumor microenvironment. J Cancer. 2021; 12(12): 3566-3574.

[255] Zheng JB, Wong CW, Liu J, et al. Glucose metabolism inhibitor PFK-015 combined with immune checkpoint inhibitor is an effective treatment regimen in cancer. OncoImmunology. 2022; 11(1):2079182.

[256] Yu X, Li W, Young KH, Li Y. Posttranslational modifications in PD-L1 turnover and function: from cradle to grave. Biomedicines. 2021; 9(11): 1702.

[257] Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015; 6(1): 6692.

[258] Li Y, Wang T, Hu X, et al. Study of KIR gene expression at the mRNA level in specific donor-derived NK cells after allogeneic HSCT. Immunogenetics. 2020; 72(3): 135-141.

[259] He W, Zhang H, Han F, et al. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 2017; 77(22): 6375-6388.

[260] Chen C, Guo Q, Fu H, et al. Asynchronous blockade of PD-L1 and CD155 by polymeric nanoparticles inhibits triple-negative breast cancer progression and metastasis. Biomaterials. 2021; 275:120988.

[261] Jia Q, Wang A, Yuan Y, Zhu B, Long H. Heterogeneity of the tumor immune microenvironment and its clinical relevance. Exp Hematol Oncol. 2022; 11(1): 24.

[262] Chen HY, Aggarwal R, Bok RA, et al. Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study. Prostate Cancer Prostatic Dis. 2020; 23(2): 269-276.

[263] Wang K, Zerdes I, Johansson HJ, et al. Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer. Nat Commun. 2024; 15(1): 3837.

[264] Vitale I, Shema E, Loi S, Galluzzi L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med. 2021; 27(2): 212-224.

[265] Yan J, Jiang Z, Zhang S, et al. Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone. Clin Transl Med. 2025; 15(2):e70224.

[266] Nunes JB, Ijsselsteijn ME, Abdelaal T, et al. Integration of mass cytometry and mass spectrometry imaging for spatially resolved single-cell metabolic profiling. Nat Methods. 2024; 21(10): 1796-1800.

[267] Horvat-Menih I, Casey R, Denholm J, et al. Probing intratumoral metabolic compartmentalisation in a patient with fumarate hydratase-deficient renal cancer using clinical hyperpolarised 13C-MRI and mass spectrometry imaging. Commun Med. 2026; 6(1): 108.

[268] Le J, Dian Y, Zhao D, et al. Single-cell multi-omics in cancer immunotherapy: from tumor heterogeneity to personalized precision treatment. Mol Cancer. 2025; 24(1): 221.

[269] Xue ZR, Xin YY, Jin WL. Exploiting metabolic vulnerabilities in cancer: from mechanisms to therapeutic opportunities. Cancer Lett. 2025; 634:218067.

RIGHTS & PERMISSIONS

2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.