Targeting Immune Cell Metabolism for Cancer Immunotherapy
DOI:
https://doi.org/10.66505/cbtt.v1i3.48Keywords:
Immunometabolism, tumor microenvironment, metabolic reprogramming, tumor-infiltrating immune cells, cancer immunotherapy, immune cell metabolism, fatty acid metabolismAbstract
Metabolic reprogramming is a fundamental regulator of immune cell fate and function in the tumor microenvironment (TME), though the relative contributions of individual metabolic pathways vary across immune cell subsets, tumor types, and disease stages. Competition for nutrients, hypoxia, and the accumulation of immunosuppressive metabolites reshape the TME's metabolic landscape, driving functional exhaustion of antitumor immune cells while promoting the persistence of immunosuppressive populations. These metabolic adaptations have emerged as critical determinants of immune evasion, therapeutic resistance, and responses to cancer immunotherapy. In this review, we examine immune cell metabolism from four complementary perspectives: the physiological metabolic programs of major immune cell populations and their remodeling within the TME; the functional consequences of metabolic reprogramming for antitumor immunity; the principal metabolic drivers, including hypoxia, nutrient competition, and suppressive metabolites; and current therapeutic strategies targeting key immunometabolic pathways, with particular emphasis on glutamine, fatty acid, and lactate metabolism. We further discuss emerging metabolic modulators, their interactions with immune checkpoint blockade, and the opportunities and limitations of combining metabolic intervention with established cancer therapies. Finally, we highlight major translational challenges, including metabolic heterogeneity, limited clinical validation, biomarker identification, and the need for standardized metabolomic and single-cell approaches to enable precision immunometabolism. A more comprehensive understanding of immune cell metabolic regulation may facilitate the development of biomarker-guided therapeutic strategies that selectively restore antitumor immunity while minimizing systemic toxicity, thereby advancing the next generation of personalized cancer immunotherapies.
References
1. Xiao Y, Yu TJ, Xu Y, Ding R, Wang YP, Jiang YZ, et al. Emerging therapies in cancer metabolism. Cell Metab. 2023;35(8):1283-1303. doi:10.1016/j.cmet.2023.07.006
2. Chen D, Zhang Y, Wang W, Chen H, Ling T, Yang R, et al. Identification and characterization of robust hepatocellular carcinoma prognostic subtypes based on an integrative metabolite-protein interaction network. Adv Sci (Weinh). 2021;8(17):2100311. doi:10.1002/advs.202100311
3. Gentric G, Kieffer Y, Mieulet V, Goundiam O, Bonneau C, Nemati F, et al. PML-regulated mitochondrial metabolism enhances chemosensitivity in human ovarian cancers. Cell Metab. 2019;29(1):156-173.e10. doi:10.1016/j.cmet.2018.09.002
4. Missiaen R, Anderson NM, Kim LC, Nance B, Burrows M, Skuli N, et al. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell Metab. 2022;34(8):1151-1167.e7. doi:10.1016/j.cmet.2022.06.010
5. Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity. 2023;56(10):2188-2205. doi:10.1016/j.immuni.2023.09.011
6. Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer. 2020;20(9):516-531. doi:10.1038/s41568-020-0273-y
7. Zhang L, Romero P. Metabolic control of CD8+ T-cell fate decisions and antitumor immunity. Trends Mol Med. 2018;24(1):30-48. doi:10.1016/j.molmed.2017.11.005
8. Nomura M, Liu J, Rovira II, Gonzalez-Hurtado E, Lee J, Wolfgang MJ, et al. Fatty acid oxidation in macrophage polarization. Nat Immunol. 2016;17(3):216-217. doi:10.1038/ni.3366
9. Xu J, Ding L, Mei J, Hu Y, Kong X, Dai S, et al. Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments. Signal Transduct Target Ther. 2025;10(1):268. doi:10.1038/s41392-025-02325-5
10. Li M, Yang Y, Xiong L, Jiang P, Wang J, Li C. Metabolism, metabolites, and macrophages in cancer. J Hematol Oncol. 2023;16(1):80. doi:10.1186/s13045-023-01478-6
11. Savage PA, Klawon DEJ, Miller CH. Regulatory T cell development. Annu Rev Immunol. 2020;38:421-453. doi:10.1146/annurev-immunol-100219-020937
12. Koh C-H, Lee S, Kwak M, Kim B-S, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med. 2023;55(11):2287-2299. doi:10.1038/s12276-023-01105-x
13. Chen Y, Xu Z, Sun H, Ouyang X, Han Y, Yu H, et al. Regulation of CD8+ T memory and exhaustion by the mTOR signals. Cell Mol Immunol. 2023;20(9):1023-1039. doi:10.1038/s41423-023-01064-3
14. Nobs SP, Kolodziejczyk AA, Adler L, Horesh N, Botscharnikow C, Herzog E, et al. Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes. Nature. 2023;624(7992):645-652. doi:10.1038/s41586-023-06803-0
15. Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021;184(3):792-809.e23. doi:10.1016/j.cell.2021.01.010
16. Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, et al. Neutrophil diversity and function in health and disease. Signal Transduct Target Ther. 2024;9(1):343. doi:10.1038/s41392-024-02049-y
17. Willson JA, Arienti S, Sadiku P, Reyes L, Coelho P, Morrison T, et al. Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle. Blood. 2022;139(2):281-286. doi:10.1182/blood.2021011010
18. Martinis E, Tonon S, Colamatteo A, La Cava A, Matarese G, Pucillo CEM. B cell immunometabolism in health and disease. Nat Immunol. 2025;26(3):366-377. doi:10.1038/s41590-025-02102-0
19. O'Brien KL, Finlay DK. Immunometabolism and natural killer cell responses. Nat Rev Immunol. 2019;19(5):282-290. doi:10.1038/s41577-019-0139-2
20. Ran GH, Lin YQ, Tian L, Zhang T, Yan DM, Yu JH, et al. Natural killer cell homing and trafficking in tissues and tumors: from biology to application. Signal Transduct Target Ther. 2022;7(1):205. doi:10.1038/s41392-022-01058-z
21. Kao K-C, Vilbois S, Tsai C-H, Ho P-C. Metabolic communication in the tumour-immune microenvironment. Nat Cell Biol. 2022;24(11):1574-1583. doi:10.1038/s41556-022-01002-x
22. Andrejeva G, Rathmell JC. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 2017;26(1):49-70. doi:10.1016/j.cmet.2017.06.004
23. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541-550. doi:10.1038/s41591-018-0014-x
24. Yang P, Qin H, Li Y, Xiao A, Zheng E, Zeng H, et al. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat Commun. 2022;13(1):5782. doi:10.1038/s41467-022-33349-y
25. Reina-Campos M, Scharping NE, Goldrath AW. CD8+ T cell metabolism in infection and cancer. Nat Rev Immunol. 2021;21(11):718-738. doi:10.1038/s41577-021-00537-8
26. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569(7755):270-274. doi:10.1038/s41586-019-1170-y
27. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022;40(4):365-378.e6. doi:10.1016/j.ccell.2022.02.003
28. Jaccard A, Wyss T, Maldonado-Pérez N, Rath JA, Bevilacqua A, Peng J-J, et al. Reductive carboxylation epigenetically instructs T cell differentiation. Nature. 2023;621(7980):849-856. doi:10.1038/s41586-023-06546-y
29. Wang H, Franco F, Tsui Y-C, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020;21(3):298-308. doi:10.1038/s41590-019-0589-5
30. Kelly B, O'Neill LAJ. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25(7):771-784. doi:10.1038/cr.2015.68
31. Yan C, Zheng L, Jiang S, Yang H, Guo J, Jiang L-Y, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell. 2023;41(7):1276-1293.e11. doi:10.1016/j.ccell.2023.04.016
32. Zhao Z, Qin J, Qian Y, Huang C, Liu X, Wang N, et al. FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion. J Hematol Oncol. 2024;17(1):9. doi:10.1186/s13045-024-01529-6
33. Sadiku P, Willson JA, Ryan EM, Sammut D, Coelho P, Watts ER, et al. Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metab. 2021;33(2):411-423.e4. doi:10.1016/j.cmet.2020.11.016
34. Tang W, Luan Y, Yuan Q, Li A, Chen S, Menacherry S, et al. LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments. Nat Commun. 2024;15(1):3068. doi:10.1038/s41467-024-47262-z
35. Wang X-Y, Wei Y, Hu B, Liao Y, Wang X, Wan W-H, et al. c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses. Signal Transduct Target Ther. 2022;7(1):105. doi:10.1038/s41392-022-00948-6
36. Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020;19(1):120. doi:10.1186/s12943-020-01238-x
37. Franco F, Jaccard A, Romero P, Yu YR, Ho P-C. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab. 2020;2(10):1001-1012. doi:10.1038/s42255-020-00280-9
38. Cao J, Liao S, Zeng F, Liao Q, Luo G, Zhou Y. Effects of altered glycolysis levels on CD8(+) T cell activation and function. Cell Death Dis. 2023;14(7):407. doi:10.1038/s41419-023-05937-3
39. Gebhardt T, Park SL, Parish IA. Stem-like exhausted and memory CD8+ T cells in cancer. Nat Rev Cancer. 2023;23(11):780-798. doi:10.1038/s41568-023-00615-0
40. Marangoni F, Zhakyp A, Corsini M, Geels SN, Carrizosa E, Thelen M, et al. Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell. 2021;184(15):3998-4015.e19. doi:10.1016/j.cell.2021.05.027
41. Hu C, You W, Kong D, Huang Y, Lu J, Zhao M, et al. Tertiary lymphoid structure-associated B cells enhance CXCL13(+)CD103(+)CD8(+) tissue-resident memory T-cell response to programmed cell death protein 1 blockade in cancer immunotherapy. Gastroenterology. 2024;166(6):1069-1084. doi:10.1053/j.gastro.2023.10.022
42. Fridman WH, Meylan M, Pupier G, Calvez A, Hernandez I, Sautès-Fridman C. Tertiary lymphoid structures and B cells: an intratumoral immunity cycle. Immunity. 2023;56(10):2254-2269. doi:10.1016/j.immuni.2023.08.009
43. Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, Fallon PG. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun. 2015;6(1):5997. doi:10.1038/ncomms6997
44. Wu H, Xia L, Jia D, Zou H, Jin G, Qian W, et al. PD-L1(+) regulatory B cells act as a T cell suppressor in a PD-L1-dependent manner in melanoma patients with bone metastasis. Mol Immunol. 2020;119:83-91. doi:10.1016/j.molimm.2020.01.008
45. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221-241. doi:10.1146/annurev-immunol-020711-074934
46. Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer. 2023;22(1):34. doi:10.1186/s12943-023-01737-7
47. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021;18(2):85-100. doi:10.1038/s41571-020-0426-7
48. Kersten K, Hu KH, Combes AJ, Samad B, Harwin T, Ray A, et al. Spatiotemporal co-dependency between macrophages and exhausted CD8(+) T cells in cancer. Cancer Cell. 2022;40(6):624-638.e9. doi:10.1016/j.ccell.2022.05.004
49. Wen Z, Sun H, Zhang Z, Zheng Y, Zheng S, Bin J, et al. High baseline tumor burden-associated macrophages promote an immunosuppressive microenvironment and reduce the efficacy of immune checkpoint inhibitors through the IGFBP2-STAT3-PD-L1 pathway. Cancer Commun (Lond). 2023;43(5):562-581. doi:10.1002/cac2.12420
50. Carbó JM, León TE, Font-Díaz J, de la Rosa JV, Castrillo A, Picard FR, et al. Pharmacologic activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment. Cancer Res. 2021;81(4):968-985. doi:10.1158/0008-5472.CAN-19-3360
51. Shapir Itai Y, Barboy O, Salomon R, Bercovich A, Xie K, Winter E, et al. Bispecific dendritic-T cell engager potentiates anti-tumor immunity. Cell. 2024;187(2):375-389.e18. doi:10.1016/j.cell.2023.12.011
52. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774. doi:10.1038/nri1457
53. Hegde S, Leader AM, Merad M. MDSC: markers, development, states, and unaddressed complexity. Immunity. 2021;54(5):875-884. doi:10.1016/j.immuni.2021.04.004
54. Wen J, Zhang X, Wong CC, Zhang Y, Pan Y, Zhou Y, et al. Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma. Gut. 2024;73(12):2023-2036. doi:10.1136/gutjnl-2023-331117
55. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-790. doi:10.1084/jem.20131916
56. Blidner AG, Bach CA, García PA, Merlo JP, Cagnoni AJ, Bannoud N, et al. Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells. Immunity. 2025;58(6):1553-1571.e8. doi:10.1016/j.immuni.2025.04.027
57. Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood. 2019;133(20):2159-2167. doi:10.1182/blood-2018-11-844548
58. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: "N1" versus "N2" TAN. Cancer Cell. 2009;16(3):183-194. doi:10.1016/j.ccr.2009.06.017
59. Adrover JM, McDowell SAC, He XY, Quail DF, Egeblad M. NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell. 2023;41(3):505-526. doi:10.1016/j.ccell.2023.02.001
60. Haykal T, Yang R, Tohme C, He Z, Liu S, Geller DA, et al. Surgery-induced neutrophil extracellular traps promote tumor metastasis by reprogramming cancer cell lipid metabolism. Cancer Res. 2025;85(24):4995-5014. doi:10.1158/0008-5472.CAN-24-3393
61. Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18(1):157. doi:10.1186/s12943-019-1089-9
62. Zhang Y, Wang J, He M, Liu J, Zhao J, He J, et al. Hypobaric hypoxia-driven energy metabolism disturbance facilitates vascular endothelial dysfunction. Redox Biol. 2025;84:103675. doi:10.1016/j.redox.2025.103675
63. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-498. doi:10.1038/s41577-020-00490-y
64. Guo C, You Z, Shi H, Sun Y, Du X, Palacios G, et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature. 2023;620(7972):200-208. doi:10.1038/s41586-023-06299-8
65. Tharp KM, Kersten K, Maller O, Timblin GA, Stashko C, Canale FP, et al. Tumor-associated macrophages restrict CD8(+) T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment. Nat Cancer. 2024;5(7):1045-1062. doi:10.1038/s43018-024-00775-4
66. Mao Y, Xia W, Jiang P. Metabolites as signalling molecules in the tumour immune microenvironment. Nat Rev Immunol. 2026;26:422-438. doi:10.1038/s41577-025-01258-y
67. Rastogi S, Mishra SS, Arora MK, Kaithwas G, Banerjee S, Ravichandiran V, et al. Lactate acidosis and simultaneous recruitment of TGF-β leads to altered plasticity of hypoxic cancer cells in the tumor microenvironment. Pharmacol Ther. 2023;250:108519. doi:10.1016/j.pharmthera.2023.108519
68. Ding R, Yu X, Hu Z, Dong Y, Huang H, Zhang Y, et al. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity. 2024;57(3):528-540.e6. doi:10.1016/j.immuni.2024.01.019
69. Li H, Sun L, Gao P, Hu H. Lactylation in cancer: current understanding and challenges. Cancer Cell. 2024;42(11):1803-1807. doi:10.1016/j.ccell.2024.09.006
70. Xia C, Yin S, To KKW, Fu L. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol Cancer. 2023;22(1):44. doi:10.1186/s12943-023-01733-x
71. Tay C, Tanaka A, Sakaguchi S. Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy. Cancer Cell. 2023;41(3):450-465. doi:10.1016/j.ccell.2023.02.014
72. Tong L, Jiménez-Cortegana C, Tay AHM, Wickström S, Galluzzi L, Lundqvist A. NK cells and solid tumors: therapeutic potential and persisting obstacles. Mol Cancer. 2022;21(1):206. doi:10.1186/s12943-022-01672-z
73. Gargaro M, Scalisi G, Manni G, Briseño CG, Bagadia P, Durai V, et al. Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication. Immunity. 2022;55(6):1032-1050.e14. doi:10.1016/j.immuni.2022.05.013
74. Zhu Y, Zhou Z, Du X, Lin X, Liang Z-M, Chen S, et al. Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion. Cancer Cell. 2025;43(6):1045-1060.e7. doi:10.1016/j.ccell.2025.03.015
75. Rivadeneira DB, Thosar S, Quann K, Gunn WG, Dean VG, Xie B, et al. Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer. Immunity. 2025;58(10):2524-2540.e5. doi:10.1016/j.immuni.2025.08.008
76. Cruz de Casas P, Knöpper K, Dey Sarkar R, Kastenmüller W. Same yet different-how lymph node heterogeneity affects immune responses. Nat Rev Immunol. 2024;24(5):358-374. doi:10.1038/s41577-023-00965-8
77. Shao N, Qiu H, Liu J, Xiao D, Zhao J, Chen C, et al. Targeting lipid metabolism of macrophages: a new strategy for tumor therapy. J Adv Res. 2025;68:99-114. doi:10.1016/j.jare.2024.02.009
78. Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022;21(1):104. doi:10.1186/s12943-022-01569-x
79. Zhang B, Vogelzang A, Miyajima M, Sugiura Y, Wu Y, Chamoto K, et al. B cell-derived GABA elicits IL-10(+) macrophages to limit anti-tumour immunity. Nature. 2021;599(7885):471-476. doi:10.1038/s41586-021-04082-1
80. van der Leun AM, Thommen DS, Schumacher TN. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020;20(4):218-232. doi:10.1038/s41568-019-0235-4
81. Shu Y, Yue J, Li Y, Yin Y, Wang J, Li T, et al. Development of human lactate dehydrogenase a inhibitors: high-throughput screening, molecular dynamics simulation, and enzyme activity assay. J Comput Aided Mol Des. 2024;38(1):28. doi:10.1007/s10822-024-00568-y
82. Purkey HE, Robarge K, Chen J, Chen Z, Corson LB, Ding CZ, et al. Cell active hydroxylactam inhibitors of human lactate dehydrogenase with oral bioavailability in mice. ACS Med Chem Lett. 2016;7(10):896-901. doi:10.1021/acsmedchemlett.6b00190
83. Oshima N, Ishida R, Kishimoto S, Beebe K, Brender JR, Yamamoto K, et al. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep. 2020;30(6):1798-1810.e4. doi:10.1016/j.celrep.2020.01.039
84. Guo L, Yang Y, Sheng Y, Wang J, Li W, Zhou X, et al. Galloflavin relieves the malignant behavior of colorectal cancer cells in the inflammatory tumor microenvironment. Front Pharmacol. 2021;12:752118. doi:10.3389/fphar.2021.752118
85. Singh M, Afonso J, Sharma D, Gupta R, Kumar V, Rani R, et al. Targeting monocarboxylate transporters (MCTs) in cancer: how close are we to the clinics? Semin Cancer Biol. 2023;90:1-14. doi:10.1016/j.semcancer.2023.01.007
86. Caslin HL, Abebayehu D, Pinette JA, Ryan JJ. Lactate is a metabolic mediator that shapes immune cell fate and function. Front Physiol. 2021;12:688485. doi:10.3389/fphys.2021.688485
87. Beloueche-Babari M, Casals Galobart T, Delgado-Goni T, Wantuch S, Parkes HG, Tandy D, et al. Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration. Br J Cancer. 2020;122(6):895-903. doi:10.1038/s41416-019-0717-x
88. Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell. 2021;184(2):370-383.e13. doi:10.1016/j.cell.2020.11.043
89. Halford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, et al. A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer. Clin Cancer Res. 2023;29(8):1429-1439. doi:10.1158/1078-0432.CCR-22-2263
90. Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8(+) T cells. Cell Metab. 2022;34(8):1137-1150.e6. doi:10.1016/j.cmet.2022.06.008
91. Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021;591(7851):645-651. doi:10.1038/s41586-020-03045-2
92. Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21(2):141-162. doi:10.1038/s41573-021-00339-6
93. Earhart RH, Amato DJ, Chang AY, Borden EC, Shiraki M, Dowd ME, et al. Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. Invest New Drugs. 1990;8(1):113-119. doi:10.1007/BF00216936
94. Magill GB, Myers WP, Reilly HC, Putnam RC, Magill JW, Sykes MP, et al. Pharmacological and initial therapeutic observations on 6-diazo-5-oxo-L-norleucine (DON) in human neoplastic disease. Cancer. 1957;10(6):1138-1150. doi:10.1002/1097-0142(195711/12)10:6<1138::aid-cncr2820100608>3.0.co;2-k
95. Ovejera AA, Houchens DP, Catane R, Sheridan MA, Muggia FM. Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-γ-glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice. Cancer Res. 1979;39(8):3220-3224. PMID: 572261
96. Ahluwalia GS, Grem JL, Hao Z, Cooney DA. Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther. 1990;46(2):243-271. doi:10.1016/0163-7258(90)90094-I
97. Lemberg KM, Vornov JJ, Rais R, Slusher BS. We're not "DON" yet: optimal dosing and prodrug delivery of 6-diazo-5-oxo-L-norleucine. Mol Cancer Ther. 2018;17(9):1824-1832. doi:10.1158/1535-7163.MCT-17-1148
98. Rais R, Jančařík A, Tenora L, Nedelcovych M, Alt J, Englert J, et al. Discovery of 6-diazo-5-oxo-L-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J Med Chem. 2016;59(18):8621-8633. doi:10.1021/acs.jmedchem.6b01069
99. Leone RD, Zhao L, Englert JM, Sun I-M, Oh M-H, Sun I-H, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019;366(6468):1013-1021. doi:10.1126/science.aav2588
100. Oh M-H, Sun I-H, Zhao L, Leone RD, Sun I-M, Xu W, et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest. 2020;130(7):3865-3884. doi:10.1172/JCI131859
101. Praharaj M, Shen F, Lee AJ, Zhao L, Nirschl TR, Theodros D, et al. Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancers. Cancer Immunol Res. 2024;12(7):854-875. doi:10.1158/2326-6066.CIR-23-1105
102. Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014;40(5):692-705. doi:10.1016/j.immuni.2014.04.007
103. Rais R, Lemberg KM, Tenora L, Arwood ML, Pal A, Alt J, et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022;8(46):eabq5925. doi:10.1126/sciadv.abq5925
104. Pillai R, LeBoeuf SE, Hao Y, New C, Blum JLE, Rashidfarrokhi A, et al. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1-mutant lung cancer. Sci Adv. 2024;10(13):eadm9859. doi:10.1126/sciadv.adm9859
105. Yokoyama Y, Estok TM, Wild R. Sirpiglenastat (DRP-104) induces antitumor efficacy through direct, broad antagonism of glutamine metabolism and stimulation of the innate and adaptive immune systems. Mol Cancer Ther. 2022;21(10):1561-1572. doi:10.1158/1535-7163.MCT-22-0282
106. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619-634. doi:10.1038/nrc.2016.71
107. Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, et al. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J. 2007;406(3):407-414. doi:10.1042/BJ20070039
108. Hartwick EW, Curthoys NP. BPTES inhibition of hGA(124-551), a truncated form of human kidney-type glutaminase. J Enzyme Inhib Med Chem. 2012;27(6):861-867. doi:10.3109/14756366.2011.622272
109. Xiang Y, Stine ZE, Xia J, Lu Y, O'Connor RS, Altman BJ, et al. Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest. 2015;125(6):2293-2306. doi:10.1172/JCI75836
110. Finlay MRV, Anderton M, Bailey A, Boyd S, Brookfield J, Cairnduff C, et al. Discovery of a thiadiazole-pyridazine-based allosteric glutaminase 1 inhibitor series that demonstrates oral bioavailability and activity in tumor xenograft models. J Med Chem. 2019;62(14):6540-6560. doi:10.1021/acs.jmedchem.9b00260
111. Shukla K, Ferraris DV, Thomas AG, Stathis M, Duvall B, Delahanty G, et al. Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors. J Med Chem. 2012;55(23):10551-10563. doi:10.1021/jm301191p
112. Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890-901. doi:10.1158/1535-7163.MCT-13-0870
113. Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, et al. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget. 2016;7(48):79722-79735. doi:10.18632/oncotarget.12944
114. Harding JJ, Telli ML, Munster P, Voss MH, Infante JR, DeMichele A, et al. A phase I dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors. Clin Cancer Res. 2021;27(18):4994-5003. doi:10.1158/1078-0432.CCR-21-1204
115. Gouda MA, Voss MH, Tawbi H, Gordon M, Tykodi SS, Lam ET, et al. A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer. ESMO Open. 2025;10(5):104536. doi:10.1016/j.esmoop.2025.104536
116. Varghese S, Pramanik S, Williams LJ, Hodges HR, Hudgens CW, Fischer GM, et al. The glutaminase inhibitor CB-839 (telaglenastat) enhances the antimelanoma activity of T cell-mediated immunotherapies. Mol Cancer Ther. 2021;20(3):500-511. doi:10.1158/1535-7163.MCT-20-0430
117. Soth MJ, Le K, Di Francesco ME, Hamilton MM, Liu G, Burke JP, et al. Discovery of IPN60090, a clinical-stage selective glutaminase-1 (GLS-1) inhibitor with excellent pharmacokinetic and physicochemical properties. J Med Chem. 2020;63(21):12957-12977. doi:10.1021/acs.jmedchem.0c01398
118. Okabe S, Moriyama M, Arai Y, Gotoh A. Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells. Cancer Biomark. 2024;41(1):55-68. doi:10.3233/CBM-230454
119. Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 2020;80(7):1438-1450. doi:10.1158/0008-5472.CAN-19-2994
120. Lilly K, Chang C, Kerner J, VanRenterghem R, Bieber LL. Effect of etomoxiryl-CoA on different carnitine acyltransferases. Biochem Pharmacol. 1992;43(2):353-361. doi:10.1016/0006-2952(92)90298-W
121. Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res. 2015;3(11):1236-1247. doi:10.1158/2326-6066.CIR-15-0036
122. Van den Bossche J, van der Windt GJW. Fatty acid oxidation in macrophages and T cells: time for reassessment? Cell Metab. 2018;28(4):538-540. doi:10.1016/j.cmet.2018.09.018
123. Moon SH, Liu X, Jenkins CM, Dilthey BG, Patti GJ, Gross RW. Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration. J Lipid Res. 2024;65(9):100611. doi:10.1016/j.jlr.2024.100611
124. Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, Ma EH, et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 2018;28(3):504-515.e7. doi:10.1016/j.cmet.2018.06.002
125. Zhang C, Yue C, Herrmann A, Song J, Egelston C, Wang T, et al. STAT3 activation-induced fatty acid oxidation in CD8+ T effector cells is critical for obesity-promoted breast tumor growth. Cell Metab. 2020;31(1):148-161.e5. doi:10.1016/j.cmet.2019.10.013
126. Dhakal B, Li CMY, Ramezanpour M, Houtak G, Li R, Bouras G, et al. Proteomic characterisation of perhexiline treatment on THP-1 M1 macrophage differentiation. Front Immunol. 2023;14:1054588. doi:10.3389/fimmu.2023.1054588
127. Dhakal B, Tomita Y, Drew P, Price T, Maddern G, Smith E, et al. Perhexiline: old drug, new tricks? A summary of its anticancer effects. Molecules. 2023;28(8):3624. doi:10.3390/molecules28083624
128. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab. 2021;33(5):1001-1012.e5. doi:10.1016/j.cmet.2021.02.015
129. Xu S, Chaudhary O, Rodríguez-Morales P, Sun X, Chen D, Zappasodi R, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity. 2021;54(7):1561-1577.e7. doi:10.1016/j.immuni.2021.05.003
130. Guerrero-Rodríguez SL, Mata-Cruz C, Pérez-Tapia SM, Velasco-Velázquez MA. Role of CD36 in cancer progression, stemness, and targeting. Front Cell Dev Biol. 2022;10:1079076. doi:10.3389/fcell.2022.1079076
131. Anderson JC, Grammer JR, Wang W, Nabors LB, Henkin J, Stewart JE, et al. ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis. Cancer Biol Ther. 2007;6(3):454-462. doi:10.4161/cbt.6.3.3630
132. Weiskopf K, Weissman IL. Macrophages are critical effectors of antibody therapies for cancer. MAbs. 2015;7(2):303-310. doi:10.1080/19420862.2015.1011450
133. Mwaikambo BR, Sennlaub F, Ong H, Chemtob S, Hardy P. Activation of CD36 inhibits and induces regression of inflammatory corneal neovascularization. Invest Ophthalmol Vis Sci. 2006;47(10):4356-4364. doi:10.1167/iovs.05-1656
134. Kuda O, Pietka TA, Demianova Z, Kudova E, Cvacka J, Kopecky J, et al. Sulfo-N-succinimidyl oleate (SSO) inhibits fatty acid uptake and signaling for intracellular calcium via binding CD36 lysine 164: SSO also inhibits oxidized low-density lipoprotein uptake by macrophages. J Biol Chem. 2013;288(22):15547-15555. doi:10.1074/jbc.M113.473298
135. Huang J, Tsang WY, Fang XN, Zhang Y, Luo J, Gong LQ, et al. FASN inhibition decreases MHC-I degradation and synergizes with PD-L1 checkpoint blockade in hepatocellular carcinoma. Cancer Res. 2024;84(6):855-871. doi:10.1158/0008-5472.CAN-23-0966
136. Tang W, Sun G, Ji GW, Feng T, Zhang Q, Cao H, et al. Single-cell RNA-sequencing atlas reveals an FABP1-dependent immunosuppressive environment in hepatocellular carcinoma. J Immunother Cancer. 2023;11(11):e007030. doi:10.1136/jitc-2023-007030
137. Rabold K, Aschenbrenner A, Thiele C, Boahen CK, Schiltmans A, Smit JWA, et al. Enhanced lipid biosynthesis in human tumor-induced macrophages contributes to their protumoral characteristics. J Immunother Cancer. 2020;8(2):e000638. doi:10.1136/jitc-2020-000638
138. Teijeira A, Garasa S, Etxeberria I, Gato-Cañas M, Melero I, Delgoffe GM. Metabolic consequences of T-cell costimulation in anticancer immunity. Cancer Immunol Res. 2019;7(10):1564-1569. doi:10.1158/2326-6066.CIR-19-0115
139. Prestipino A, Emhardt AJ, Aumann K, O'Sullivan D, Gorantla SP, Duquesne S, et al. Oncogenic JAK2(V617F) causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med. 2018;10(429):eaam7729. doi:10.1126/scitranslmed.aam7729
140. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-9553. doi:10.1128/MCB.25.21.9543-9553.2005
141. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, 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. doi:10.1038/ncomms7692
142. Klein Geltink RI, O'Sullivan D, Corrado M, Bremser A, Buck MD, Buescher JM, et al. Mitochondrial priming by CD28. Cell. 2017;171(2):385-397.e11. doi:10.1016/j.cell.2017.08.018
143. O'Sullivan D, Sanin DE, Pearce EJ, Pearce EL. Metabolic interventions in the immune response to cancer. Nat Rev Immunol. 2019;19(5):324-335. doi:10.1038/s41577-019-0140-9
144. Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018;215(4):1091-1100. doi:10.1084/jem.20171068
145. Pai JA, Hellmann MD, Sauter JL, Mattar M, Rizvi H, Woo HJ, et al. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell. 2023;41(4):776-790.e7. doi:10.1016/j.ccell.2023.03.009
146. Fan C, Zhang S, Gong Z, Li X, Xiang B, Deng H, et al. Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy. Sci China Life Sci. 2021;64(4):534-547. doi:10.1007/s11427-019-1735-4
147. Xiao Z, Dai Z, Locasale JW. Metabolic landscape of the tumor microenvironment at single-cell resolution. Nat Commun. 2019;10(1):3763. doi:10.1038/s41467-019-11738-0
148. Park J, Hsueh PC, Li Z, Ho P-C. Microenvironment-driven metabolic adaptations guiding CD8(+) T cell anti-tumor immunity. Immunity. 2023;56(1):32-42. doi:10.1016/j.immuni.2022.12.008
149. Reznik E, Luna A, Aksoy BA, Liu EM, La K, Ostrovnaya I, et al. A landscape of metabolic variation across tumor types. Cell Syst. 2018;6(3):301-313.e3. doi:10.1016/j.cels.2017.12.014
150. DiNardo CD, Verma D, Baran N, Bhagat TD, Skwarska A, Lodi A, et al. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses. Nat Cancer. 2024;5(10):1515-1533. doi:10.1038/s43018-024-00811-3
151. Florio R, De Lellis L, Veschi S, Verginelli F, Di Giacomo V, Gallorini M, et al. Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells. Sci Rep. 2018;8(1):13610. doi:10.1038/s41598-018-31797-5
152. Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 2020;30(6):465-474. doi:10.1038/s41422-020-0324-7
153. Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22(10):557-575. doi:10.1038/s41568-022-00491-0
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Yi-Qing Jiang, Yan-Ling Wu, Tian-Lei Ying
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright
Authors publishing in Cancer Biome and Targeted Therapy retain full copyright of their work. By submitting a manuscript, authors grant the publisher (GCINC Press) a non-exclusive license to publish, distribute, and archive the article, and to identify itself as the original publisher.
License
All articles are published open access under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0).
https://creativecommons.org/licenses/by/4.0/. This license permits unrestricted use, distribution, reproduction, and adaptation in any medium, including for commercial purposes, provided that:
- Proper attribution is given to the original author(s) and source,
- A link to the license is provided, and
- Any changes made are clearly indicated.
Author Rights
Authors retain the right to:
- Use their article in future works (e.g., books, theses, lectures)
- Share and archive the final published version on institutional repositories or personal websites
- Adapt or translate their work, or authorize others to do so, with proper citation
Reuse by Third Parties
Content is licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). Third parties may copy, redistribute, remix, transform, and build upon the material for any purpose, including commercial use, provided that appropriate credit is given to the original author(s).
Archiving and Preservation
All articles are made freely available immediately upon publication, without embargo. Cancer Biome and Targeted Therapy is hosted on the Open Journal Systems (OJS) platform, developed by the Public Knowledge Project (PKP). The journal participates in long-term digital preservation through the PKP Preservation Network (PKP PN) using the LOCKSS system. Authors are encouraged to self-archive in institutional repositories, disciplinary archives, and preprint servers in accordance with the license terms.
