journal article·2026-03-04Open access

Molecular Targets for Cancer Immunotherapy: Focusing on (Immune and Tumor) Cell-Derived Metabolites

Rafaella Delatorre Tavares Quintans, Ângelo Azevedo de Freitas, Maynah Melo de Souza, Geovane Dias-Lopes, Rafael Cardoso Maciel Costa Silva

Applied Sciences· Volume 16· Issue 5

Abstract

Tumor cells from different organs possess distinct metabolic requirements and develop in specific microenvironments. In this context, metabolites from the tumor microenvironment may impact the biology of tumors. Carbohydrates, lipids, and other metabolic intermediates exhibit important (and often contradictory) functions in the tumor microenvironment. Here, several metabolites are discussed according to their role in both tumor and immune cell biology and how they can promote tumor growth or regression in distinct circumstances. In this context, numerous studies have highlighted that the combination of immunotherapies, including modulators of metabolic processes, emerges as a promising therapeutic strategy for treating distinct tumors. This combination might be especially important to impair the emergence of resistant clones of tumor cells and will be discussed in this review.
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Research context

OpenAlex topics: Cancer, Hypoxia, and Metabolism · Cancer Research and Treatments · Cancer, Lipids, and Metabolism

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Faculty of Medical Sciences, State University of Rio de Janeiro, Cabo Frio 20550-013, Brazil

Funding

Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior—CAPES · Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro—FAPERJ

References (100+)

Show source-provided references
1. The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition10.1038/ncomms15503 ↗
2. The lipid metabolism remodeling: A hurdle in breast cancer therapy10.1016/j.canlet.2023.216512 ↗
3. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type10.1016/j.cmet.2011.12.015 ↗
4. Sugár, S., Bugyi, F., Tóth, G., Pápay, J., Kovalszky, I., Tornóczky, T., Drahos, L., and Turiák, L. (2022). Proteomic Analysis of Lung Cancer Types—A Pilot Study. Cancers, 14.10.3390/cancers14112629 ↗
5. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models10.1172/JCI177606 ↗
6. Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy10.1016/j.celrep.2020.01.039 ↗
7. Repurposing glucose-lowering drugs for cancer therapy10.1016/j.trecan.2025.04.010 ↗
8. Morris, R.M., Mortimer, T.O., and O’Neill, K.L. (2022). Cytokines: Can Cancer Get the Message?. Cancers, 14.10.3390/cancers14092178 ↗
9. What comes next in glycobiology10.1016/j.cell.2024.04.028 ↗
10. Cancer cell metabolism and antitumour immunity10.1038/s41577-024-01026-4 ↗
11. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants10.1038/ni.3269 ↗
12. Malonylation of GAPDH is an inflammatory signal in macrophages10.1038/s41467-018-08187-6 ↗
13. Godfrey, W.H., and Kornberg, M.D. (2020). The Role of Metabolic Enzymes in the Regulation of Inflammation. Metabolites, 10.10.3390/metabo10110426 ↗
14. Metabolic reprogramming in macrophage responses10.1186/s40364-020-00251-y ↗
15. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control10.1016/j.cmet.2025.07.006 ↗
16. The glucose transporter 2 regulates CD8+ T cell function via environment sensing10.1038/s42255-023-00913-9 ↗
17. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy10.1038/s41467-021-21099-2 ↗
18. Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner10.1016/j.biopha.2022.113171 ↗
19. CD28 co-stimulation stabilizes the expression of the CD40 ligand on T cells10.1093/intimm/10.8.1083 ↗
20. PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy?10.1080/2162402X.2017.1364828 ↗
21. Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis10.1016/j.isci.2022.105004 ↗
22. Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy?10.1038/nrc.2016.77 ↗
23. Kim, J., Lee, H., Choi, H.K., and Min, H. (2023). Discovery of Myeloid-Derived Suppressor Cell-Specific Metabolism by Metabolomic and Lipidomic Profiling. Metabolites, 13.10.3390/metabo13040477 ↗
24. Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation10.1038/s42255-024-01201-w ↗
25. Organ- and cell-type specific delivery of kinase inhibitors: A novel approach in the development of targeted drugs
26. Galal, M.A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S., and Aljada, A. (2024). Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int. J. Mol. Sci., 25.10.3390/ijms25074083 ↗
27. Harnessing innate immune pathways for therapeutic advancement in cancer10.1038/s41392-024-01765-9 ↗
28. Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT310.1038/s41598-023-28576-2 ↗
29. Targeting Strategies for Tissue-Specific Drug Delivery10.1016/j.cell.2020.02.001 ↗
30. Engineering precision nanoparticles for drug delivery10.1038/s41573-020-0090-8 ↗
31. Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL10.1016/j.cell.2025.06.027 ↗
32. Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy10.1016/j.cmet.2018.02.024 ↗
33. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα10.1016/j.cmet.2022.08.002 ↗
34. Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer10.1016/j.cmet.2018.04.022 ↗
35. Nutrient-driven histone code determines exhausted CD8+ T cell fates10.1126/science.adj3020 ↗
36. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy10.1038/s41590-024-01963-1 ↗
37. Discovery of novel ataxia telangiectasia mutated (ATM) kinase modulators: Computational simulation, biological evaluation and cancer combinational chemotherapy study10.1016/j.ejmech.2022.114196 ↗
38. Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells10.1016/j.cmet.2025.06.011 ↗
39. Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases10.1016/j.pharmthera.2017.02.030 ↗
40. Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression10.1002/mnfr.201500759 ↗
41. Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation10.1007/s00702-008-0126-4 ↗
42. Advanced glycation end products induce T cell apoptosis: Involvement of oxidative stress, caspase and the mitochondrial pathway10.1016/j.mad.2010.09.005 ↗
43. AGEs-RAGE manipulates tumor intrinsic pERK/Sp1/IL6 pathway and reprograms macrophage to promote intrahepatic cholangiocarcinoma progression10.1016/j.tranon.2025.102446 ↗
44. Increased HIF-1α expression in T cells and associated with enhanced Th17 pathway in systemic lupus erythematosus10.1016/j.jfma.2022.05.003 ↗
45. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy10.1016/j.cmet.2018.09.020 ↗
46. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function10.1016/j.cmet.2014.05.004 ↗
47. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression10.1038/ni.3577 ↗
48. Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes10.1016/j.cmet.2024.10.004 ↗
49. GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy10.1158/0008-5472.CAN-20-2870 ↗
50. Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin: Role of mammalian target of rapamycin, protein kinase b, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation10.1074/jbc.274.46.33085 ↗
51. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer10.1038/s41586-024-08258-3 ↗
52. High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming10.1038/s41392-025-02359-9 ↗
53. Richardson, J.R., Schöllhorn, A., Gouttefangeas, C., and Schuhmacher, J. (2021). CD4+ T Cells: Multitasking Cells in the Duty of Cancer Immunotherapy. Cancers, 13.10.3390/cancers13040596 ↗
54. Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity10.1016/j.ccell.2024.11.003 ↗
55. Mannose inhibits proliferation and promotes apoptosis to enhance sensitivity of glioma cells to temozolomide through Wnt/β-catenin signaling pathway10.1016/j.neuint.2022.105348 ↗
56. CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation10.1084/jem.20201963 ↗
57. The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity10.1080/19420862.2018.1466767 ↗
58. Blanas, A., Sahasrabudhe, N.M., Rodríguez, E., van Kooyk, Y., and van Vliet, S.J. (2018). Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy. Front. Oncol., 8, Erratum in Front. Oncol. 2018, 8, 150. https://doi.org/10.3389/fonc.2018.00150.10.3389/fonc.2018.00039 ↗
59. Biological functions of fucose in mammals10.1093/glycob/cwx034 ↗
60. Fucosylation in cancer biology and its clinical applications10.1016/bs.pmbts.2019.01.002 ↗
61. MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma10.1038/s41467-025-56392-x ↗
62. Aberrant L-Fucose Accumulation and Increased Core Fucosylation Are Metabolic Liabilities in Mesenchymal Glioblastoma10.1158/0008-5472.CAN-22-0677 ↗
63. Fucosylation Enhances the Efficacy of Adoptively Transferred Antigen-Specific Cytotoxic T Lymphocytes10.1158/1078-0432.CCR-18-1527 ↗
64. Liang, W., Mao, S., Sun, S., Li, M., Li, Z., Yu, R., Ma, T., Gu, J., Zhang, J., and Taniguchi, N. (2018). Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation. Front. Immunol., 9.10.3389/fimmu.2018.00078 ↗
65. Phospholipase signalling networks in cancer10.1038/nrc3379 ↗
66. Cellular fatty acid metabolism and cancer10.1016/j.cmet.2013.05.017 ↗
67. Dysregulation of sphingolipid metabolism in cancer10.4161/cbt.11.2.14624 ↗
68. Sphingolipids in cancer10.1007/s10555-011-9304-1 ↗
69. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer10.1038/s41586-024-07787-1 ↗
70. IL-10 constrains sphingolipid metabolism to limit inflammation10.1038/s41586-024-07098-5 ↗
71. Eicosanoids and cancer10.1038/nrc2809 ↗
72. Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer10.1016/j.immuni.2025.03.002 ↗
73. Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation10.1016/j.cmet.2025.05.013 ↗
74. Cancer immunology data engine reveals secreted AOAH as a potential immunotherapy10.1016/j.cell.2025.07.004 ↗
75. The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8+ T cell exhaustion10.1038/s41590-025-02185-9 ↗
76. Prostacyclin receptor in tumor endothelial cells promotes angiogenesis in an autocrine manner10.1111/j.1349-7006.2012.02261.x ↗
77. Antimetastatic action of the prostacyclin analogue cicaprost in experimental mammary tumors10.1007/BF01803791 ↗
78. Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis10.1006/bbrc.1999.1840 ↗
79. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A210.1172/JCI121985 ↗
80. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity10.1038/s41586-025-08626-7 ↗
81. PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo10.1126/sciadv.aar8320 ↗
82. Exosomal PGE2 from M2 macrophages inhibits neutrophil recruitment and NET formation through lipid mediator class switching in sepsis10.1186/s12929-023-00957-9 ↗
83. PGE2-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment10.1016/j.celrep.2022.110914 ↗
84. Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling10.1111/imm.13417 ↗
85. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway10.4049/jimmunol.1202462 ↗
86. Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer10.1038/s41467-022-35584-9 ↗
87. Cancer cells impair monocyte-mediated T cell stimulation to evade immunity10.1038/s41586-024-08257-4 ↗
88. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity10.1158/1078-0432.CCR-14-0635 ↗
89. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells10.1038/s41586-024-07254-x ↗
90. Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells10.1038/s41467-024-53706-3 ↗
91. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function10.1038/s41586-024-07352-w ↗
92. Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 310.1016/j.jaci.2015.06.030 ↗
93. Prostaglandin E2 limits arachidonic acid availability and inhibits leukotriene B4 synthesis in rat alveolar macrophages by a nonphospholipase A2 mechanism10.4049/jimmunol.151.4.2096 ↗
94. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells10.1016/j.plefa.2009.01.006 ↗
95. Prostaglandin E2/leukotriene B4 balance induced by Lutzomyia longipalpis saliva favors Leishmania infantum infection10.1186/s13071-014-0601-8 ↗
96. Chen, C., Guan, J., Gu, X., Chu, Q., and Zhu, H. (2022). Prostaglandin E2 and Receptors: Insight Into Tumorigenesis, Tumor Progression, and Treatment of Hepatocellular Carcinoma. Front. Cell. Dev. Biol., 10.10.3389/fcell.2022.834859 ↗
97. Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities10.1158/1541-7786.MCR-10-0003 ↗
98. The yin and yang of leukotriene B4 mediated inflammation in cancer10.1016/j.smim.2017.09.005 ↗
99. Expression of leukotriene B4 receptor-1 on CD8+ T cells is required for their migration into tumors to elicit effective antitumor immunity10.4049/jimmunol.1300967 ↗
100. Role of leukotriene B4 in celecoxib-mediated anticancer effect10.1016/j.bbrc.2010.10.022 ↗